Bio

Academic Appointments


Professional Education


  • Ph.D., Yale University, Chemistry (1973)
  • B.S., Wilkes College, Chemistry (1969)

Patents


  • Paul Wender, Jung-Min Kee, Jeffrey Warrington. "United States Patent 8,067,632 A Process to Produce Prostratin and Structural or Functional Analogs Thereof", Leland Stanford Junior University, Nov 29, 2011
  • Christina Cooley, Erika Geihe Stanzl, Robert Waymouth, Paul Wender. "United States Patent 61,531,495 Amphipathic Co-Oligomers for the Delivery of SIRNA", Leland Stanford Junior University, Sep 11, 2011
  • Paul Wender, Lars Heumann, Rainer Kramer, Carolyn Gauntlett, Elizabeth Beans. "United States Patent 12/839,808 Prostratin Analogs, Bryostatin Analogs, Prodrugs, Synthetic Methods, and Methods of Use", Leland Stanford Junior University, Jul 20, 2010

Research & Scholarship

Current Research and Scholarly Interests


Molecular imaging, therapeutics, drug delivery, drug mode of action, synthesis

Teaching

2014-15 Courses


Graduate and Fellowship Programs


Publications

All Publications


  • Tetramethyleneethane Equivalents: Recursive Reagents for Serialized Cycloadditions. Journal of the American Chemical Society Wender, P. A., Jeffreys, M. S., Raub, A. G. 2015; 137 (28): 9088-9093

    Abstract

    New reactions and reagents that allow for multiple bond-forming events per synthetic operation are required to achieve structural complexity and thus value with step-, time-, cost-, and waste-economy. Here we report a new class of reagents that function like tetramethyleneethane (TME), allowing for back-to-back [4 + 2] cycloadditions, thereby amplifying the complexity-increasing benefits of Diels-Alder and metal-catalyzed cycloadditions. The parent recursive reagent, 2,3-dimethylene-4-trimethylsilylbutan-1-ol (DMTB), is readily available from the metathesis of ethylene and THP-protected 4-trimethylsilylbutyn-1-ol. DMTB and related reagents engage diverse dienophiles in an initial Diels-Alder or metal-catalyzed [4 + 2] cycloaddition, triggering a subsequent vinylogous Peterson elimination that recursively generates a new diene for a second cycloaddition. Overall, this multicomponent catalytic cascade produces in one operation carbo- and heterobicyclic building blocks for the synthesis of a variety of natural products, therapeutic leads, imaging agents, and materials. Its application to the three step synthesis of a new solvatochromic fluorophore, N-ethyl(6-N,N-dimethylaminoanthracene-2,3-dicarboximide) (6-DMA), and the photophysical characterization of this fluorophore are described.

    View details for DOI 10.1021/jacs.5b04091

    View details for PubMedID 25961416

  • Studies on the regio- and diastereo-selective epwddation of daphnanes and tiglianes TETRAHEDRON LETTERS Boudreault, P., Mattler, J. K., Wender, P. A. 2015; 56 (23): 3423-3427
  • Toward a Biorelevant Structure of Protein Kinase C Bound Modulators: Design, Synthesis, and Evaluation of Labeled Bryostatin Analogues for Analysis with Rotational Echo Double Resonance NMR Spectroscopy JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Loy, B. A., Lesser, A. B., Staveness, D., Billingsley, K. L., Cegelski, L., Wender, P. A. 2015; 137 (10): 3678-3685

    Abstract

    Protein kinase C (PKC) modulators are currently of great importance in preclinical and clinical studies directed at cancer, immunotherapy, HIV eradication, and Alzheimer's disease. However, the bound conformation of PKC modulators in a membrane environment is not known. Rotational echo double resonance (REDOR) NMR spectroscopy could uniquely address this challenge. However, REDOR NMR requires strategically labeled, high affinity ligands to determine interlabel distances from which the conformation of the bound ligand in the PKC-ligand complex could be identified. Here we report the first computer-guided design and syntheses of three bryostatin analogues strategically labeled for REDOR NMR analysis. Extensive computer analyses of energetically accessible analogue conformations suggested preferred labeling sites for the identification of the PKC-bound conformers. Significantly, three labeled analogues were synthesized, and, as required for REDOR analysis, all proved highly potent with PKC affinities (?1 nM) on par with bryostatin. These potent and strategically labeled bryostatin analogues are new structural leads and provide the necessary starting point for projected efforts to determine the PKC-bound conformation of such analogues in a membrane environment, as needed to design new PKC modulators and understand PKC-ligand-membrane structure and dynamics.

    View details for DOI 10.1021/jacs.5600886

    View details for Web of Science ID 000351420800039

    View details for PubMedID 25710634

  • Guanidinium-Rich, Glycerol-Derived Oligocarbonates: A New Class of Cell-Penetrating Molecular Transporters That Complex, Deliver, and Release siRNA. Molecular pharmaceutics Wender, P. A., Huttner, M. A., Staveness, D., Vargas, J. R., Xu, A. F. 2015; 12 (3): 742-750

    Abstract

    A highly versatile and step-economical route to a new class of guanidinium-rich molecular transporters and evaluation of their ability to complex, deliver, and release siRNA are described. These new drug/probe delivery systems are prepared in only two steps, irrespective of length or composition, using an organocatalytic ring-opening co-oligomerization of glycerol-derived cyclic carbonate monomers incorporating either protected guanidine or lipid side chains. The resultant amphipathic co-oligomers are highly effective vehicles for siRNA delivery, providing an excellent level of target protein suppression (>85%). These new oligocarbonates are nontoxic at levels required for cell penetration and can be tuned for particle size. Relative to the previously reported methyl(trimethylene)carbonate (MTC) scaffold, the ether linkage at C2 in the new transporters markedly enhances the stability of the siRNA/co-oligomer complexes. Both hybrid co-oligomers, containing a mixture of glycerol- and MTC-derived monomers, and co-oligomers containing only glycerol monomers are found to provide tunable control over siRNA complex stability. On the basis of a glycerol and CO2 backbone, these new co-oligomers represent a rapidly tunable and biocompatible siRNA delivery system that is highly effective in suppressing target protein synthesis.

    View details for DOI 10.1021/mp500581r

    View details for PubMedID 25588140

  • Function through Synthesis-Informed Design ACCOUNTS OF CHEMICAL RESEARCH Wender, P. A., Quiroz, R. V., Stevens, M. C. 2015; 48 (3): 752-760

    Abstract

    In 1996, a snapshot of the field of synthesis was provided by many of its thought leaders in a Chemical Reviews thematic issue on "Frontiers in Organic Synthesis". This Accounts of Chemical Research thematic issue on "Synthesis, Design, and Molecular Function" is intended to provide further perspective now from well into the 21st century. Much has happened in the past few decades. The targets, methods, strategies, reagents, procedures, goals, funding, practices, and practitioners of synthesis have changed, some in dramatic ways as documented in impressive contributions to this issue. However, a constant for most synthesis studies continues to be the goal of achieving function with synthetic economy. Whether in the form of new catalysts, reagents, therapeutic leads, diagnostics, drug delivery systems, imaging agents, sensors, materials, energy generation and storage systems, bioremediation strategies, or molecules that challenge old theories or test new ones, the function of a target has been and continues to be a major and compelling justification for its synthesis. While the targets of synthesis have historically been heavily represented by natural products, increasingly design, often inspired by natural structures, is providing a new source of target structures exhibiting new or natural functions and new or natural synthetic challenges. Complementing isolation and screening approaches to new target identification, design enables one to create targets de novo with an emphasis on sought-after function and synthetic innovation with step-economy. Design provides choice. It allows one to determine how close a synthesis will come to the ideal synthesis and how close a structure will come to the ideal function. In this Account, we address studies in our laboratory on function-oriented synthesis (FOS), a strategy to achieve function by design and with synthetic economy. By starting with function rather than structure, FOS places an initial emphasis on target design, thereby harnessing the power of chemists and computers to create new structures with desired functions that could be prepared in a simple, safe, economical, and green, if not ideal, fashion. Reported herein are examples of FOS associated with (a) molecular recognition, leading to the first designed phorbol-inspired protein kinase C regulatory ligands, the first designed bryostatin analogs, the newest bryologs, and a new family of designed kinase inhibitors, (b) target modification, leading to highly simplified but functionally competent photonucleases-molecules that cleave DNA upon photoactivation, (c) drug delivery, leading to cell penetrating molecular transporters, molecules that ferry other attached or complexed molecules across biological barriers, and (d) new reactivity-regenerating reagents in the form of functional equivalents of butatrienes, reagents that allow for back-to-back three-component cycloaddition reactions, thus achieving structural complexity and value with step-economy. While retrosynthetic analysis seeks to identify the best way to make a target, retrofunction analysis seeks to identify the best targets to make. In essence, form (structure) follows function.

    View details for DOI 10.1021/acs.accounts.5b00004

    View details for Web of Science ID 000351326900027

    View details for PubMedID 25742599

  • Catalytic Efficiency Is a Function of How Rhodium(I) (5+2) Catalysts Accommodate a Conserved Substrate Transition State Geometry: Induced Fit Model for Explaining Transition Metal Catalysis ACS CATALYSIS Mustard, T. J., Wender, P. A., Cheong, P. H. 2015; 5 (3): 1758-1763

    View details for DOI 10.1021/cs501828e

    View details for Web of Science ID 000350843500044

  • Reactivity and Chemoselectivity of Allenes in Rh(I)-Catalyzed Intermolecular (5+2) Cycloadditions with Vinylcyclopropanes: Allene-Mediated Rhodacycle Formation Can Poison Rh(I)-Catalyzed Cycloadditions JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Hong, X., Stevens, M. C., Liu, P., Wender, P. A., Houk, K. N. 2014; 136 (49): 17273-17283

    Abstract

    Allenes are important 2? building blocks in organic synthesis and engage as 2-carbon components in many metal-catalyzed reactions. Wender and co-workers discovered that methyl substituents on the terminal allene double bond counterintuitively change the reactivities of allenes in [Rh(CO)2Cl]2-catalyzed intermolecular (5 + 2) cycloadditions with vinylcyclopropanes (VCPs). More sterically encumbered allenes afford higher cycloadduct yields, and such effects are also observed in other Rh(I)-catalyzed intermolecular cycloadditions. Through density functional theory calculations (B3LYP and M06) and experiment, we explored this enigmatic reactivity and selectivity of allenes in [Rh(CO)2Cl]2-catalyzed intermolecular (5 + 2) cycloadditions with VCPs. The apparent low reactivity of terminally unsubstituted allenes is associated with a competing allene dimerization that irreversibly sequesters rhodium. With terminally substituted allenes, steric repulsion between the terminal substituents significantly increases the barrier of allene dimerization while the barrier of the (5 + 2) cycloaddition is not affected, and thus the cycloaddition prevails. Computation has also revealed the origin of chemoselectivity in (5 + 2) cycloadditions with allene-ynes. Although simple allene and acetylene have similar reaction barriers, intermolecular (5 + 2) cycloadditions of allene-ynes occur exclusively at the terminal allene double bond. The terminal double bond is more reactive due to the enhanced d-?* backdonation. At the same time, insertion of the internal double bond of an allene-yne has a higher barrier as it would break ? conjugation. Substituted alkynes are more difficult to insert compared with acetylene, because of the steric repulsion from the additional substituents. This leads to the greater reactivity of the allene double bond relative to the alkynyl group in allene-ynes.

    View details for DOI 10.1021/ja5098308

    View details for Web of Science ID 000346544200044

    View details for PubMedID 25379606

  • Computer-Guided Design, Synthesis, and Protein Kinase C Affinity of a New. Salicylate-Based Class of Bryostatin Analogs ORGANIC LETTERS Wender, P. A., Nakagawa, Y., Near, K. E., Staveness, D. 2014; 16 (19): 5136-5139

    View details for DOI 10.1021/ol502491f

    View details for Web of Science ID 000342719500043

  • Improved Protein Kinase C Affinity through Final Step Diversification of a Simplified Salicylate-Derived Bryostatin Analog Scaffold ORGANIC LETTERS Wender, P. A., Staveness, D. 2014; 16 (19): 5140-5143

    View details for DOI 10.1021/ol502492b

    View details for Web of Science ID 000342719500044

  • Cell-penetrating, guanidinium-rich molecular transporters for overcoming efflux-mediated multidrug resistance. Molecular pharmaceutics Vargas, J. R., Stanzl, E. G., Teng, N. N., Wender, P. A. 2014; 11 (8): 2553-2565

    Abstract

    Multidrug resistance (MDR) is a major cause of chemotherapy failure in the clinic. Drugs that were once effective against na´ve disease subsequently prove ineffective against recurrent disease, which often exhibits an MDR phenotype. MDR can be attributed to many factors; often dominating among these is the ability of a cell to suppress or block drug entry through upregulation of membrane-bound drug efflux pumps. Efflux pumps exhibit polyspecificity, recognizing and exporting many different types of drugs, especially those whose lipophilic nature contributes to residence in the membrane. We have developed a general strategy to overcome efflux-based resistance. This strategy involves conjugating a known drug that succumbs to efflux-mediated resistance to a cell-penetrating molecular transporter, specifically, the cell-penetrating peptide (CPP), d-octaarginine. The resultant conjugates are discrete single entities (not particle mixtures) and highly water-soluble. They rapidly enter cells, are not substrates for efflux pumps, and release the free drug only after cellular entry at a rate controlled by linker design and favored by target cell chemistry. This general strategy can be applied to many classes of drugs and allows for an exceptionally rapid advance to clinical testing, especially of drugs that succumb to resistance. The efficacy of this strategy has been successfully demonstrated with Taxol in cellular and animal models of resistant cancer and with ex vivo samples from patients with ovarian cancer. Next generation efforts in this area will involve the extension of this strategy to other chemotherapeutics and other MDR-susceptible diseases.

    View details for DOI 10.1021/mp500161z

    View details for PubMedID 24798708

  • Bioengineered Vaults: Self-Assembling Protein Shell-Lipophilic Core Nanoparticles for Drug Delivery ACS NANO Buehler, D. C., Marsden, M. D., Shen, S., Toso, D. B., Wu, X., Loo, J. A., Zhou, Z. H., Kickhoefer, V. A., Wender, P. A., Zack, J. A., Rome, L. H. 2014; 8 (8): 7723-7732

    Abstract

    We report a novel approach to a new class of bioengineered, monodispersed, self-assembling vault nanoparticles consisting of a protein shell exterior with a lipophilic core interior designed for drug and probe delivery. Recombinant vaults were engineered to contain a small amphipathic ?-helix derived from the nonstructural protein 5A of hepatitis C virus, thereby creating within the vault lumen a lipophilic microenvironment into which lipophilic compounds could be reversibly encapsulated. Multiple types of electron microscopy showed that attachment of this peptide resulted in larger than expected additional mass internalized within the vault lumen attributable to incorporation of host lipid membrane constituents spanning the vault waist (>35 nm). These bioengineered lipophilic vaults reversibly associate with a sample set of therapeutic compounds, including all-trans retinoic acid, amphotericin B, and bryostatin 1, incorporating hundreds to thousands of drug molecules per vault nanoparticle. Bryostatin 1 is of particular therapeutic interest because of its ability to potently induce expression of latent HIV, thus representing a preclinical lead in efforts to eradicate HIV/AIDS. Vaults loaded with bryostatin 1 released free drug, resulting in activation of HIV from provirus latency in vitro and induction of CD69 biomarker expression following intravenous injection into mice. The ability to preferentially and reversibly encapsulate lipophilic compounds into these novel bioengineered vault nanoparticles greatly advances their potential use as drug delivery systems.

    View details for DOI 10.1021/nn5002694

    View details for Web of Science ID 000340992300017

    View details for PubMedID 25061969

  • Propargyltrimethylsilanes as Allene Equivalents in Transition Metal-Catalyzed [5+2] Cycloadditions ORGANIC LETTERS Wender, P. A., Inagaki, F., Pfaffenbach, M., Stevens, M. C. 2014; 16 (11): 2923-2925

    Abstract

    Conventional allenes have not been effective ?-reactive 2-carbon components in many intermolecular cycloadditions including metal-catalyzed [5 + 2] cycloadditions. We report herein that rhodium-catalyzed [5 + 2] cycloadditions of propargyltrimethylsilanes and vinylcyclopropanes provide, after in situ protodesilylation, a highly efficient route to formal allene cycloadducts. Propargyltrimethylsilanes function as safe, easily handled synthetic equivalents of gaseous allenes and hard-to-access monosubstituted allenes. In this one-flask procedure, they provide cycloadducts of what is formally addition to the more sterically encumbered allene double bond.

    View details for DOI 10.1021/ol501114q

    View details for Web of Science ID 000337074300036

    View details for PubMedID 24819093

  • Structural complexity through multicomponent cycloaddition cascades enabled by dual-purpose, reactivity regenerating 1,2,3-triene equivalents NATURE CHEMISTRY Wender, P. A., Fournogerakis, D. N., Jeffreys, M. S., Quiroz, R. V., Inagaki, F., Pfaffenbach, M. 2014; 6 (5): 448-452

    Abstract

    Multicomponent reactions allow for more bond-forming events per synthetic operation, enabling more step- and time-economical conversion of simple starting materials to complex and thus value-added targets. These processes invariably require that reactivity be relayed from intermediate to intermediate over several mechanistic steps until a termination event produces the final product. Here, we report a multicomponent process in which a novel 1,2,3-butatriene equivalent (TMSBO: TMSCH2C?CCH2OH) engages chemospecifically as a two-carbon alkyne component in a metal-catalysed [5 + 2] cycloaddition with a vinylcyclopropane to produce an intermediate cycloadduct. Under the reaction conditions, this intermediate undergoes a remarkably rapid 1,4-Peterson elimination, producing a reactive four-carbon diene intermediate that is readily intercepted in either a metal-catalysed or thermal [4 + 2] cycloaddition. TMSBO thus serves as an yne-to-diene transmissive reagent coupling two powerful and convergent cycloadditions--the homologous Diels-Alder and Diels-Alder cycloadditions--through a vinylogous Peterson elimination, and enabling flexible access to diverse polycycles.

    View details for DOI 10.1038/NCHEM.1917

    View details for Web of Science ID 000334919700017

    View details for PubMedID 24755598

  • Toward the ideal synthesis and molecular function through synthesis-informed design NATURAL PRODUCT REPORTS Wender, P. A. 2014; 31 (4): 433-440

    Abstract

    This Highlight describes factors that contribute to an ideal synthesis, including economies (step, time, atom, solvent, energy) and orientations (target, diversity, safety, function), and the role of synthesis-informed design directed at function in advancing synthesis and its impact on science.

    View details for DOI 10.1039/c4np00013g

    View details for Web of Science ID 000333040900004

    View details for PubMedID 24589860

  • Fifteen Years of Cell-Penetrating Guanidinium-Rich Molecular Transporters: Basic Science, Research Tools, and Clinical Applications ACCOUNTS OF CHEMICAL RESEARCH Stanzl, E. G., Trantow, B. M., Vargas, J. R., Wender, P. A. 2013; 46 (12): 2944-2954

    Abstract

    All living systems require biochemical barriers. As a consequence, all drugs, imaging agents, and probes have targets that are either on, in, or inside of these barriers. Fifteen years ago, we initiated research directed at more fully understanding these barriers and at developing tools and strategies for breaching them that could be of use in basic research, imaging, diagnostics, and medicine. At the outset of this research and now to a lesser extent, the "rules" for drug design biased the selection of drug candidates mainly to those with an intermediate and narrow log P. At the same time, it was becoming increasingly apparent that Nature had long ago developed clever strategies to circumvent these "rules." In 1988, for example, independent reports documented the otherwise uncommon passage of a protein (HIV-Tat) across a membrane. A subsequent study implicated a highly basic domain in this protein (Tat49-57) in its cellular entry. This conspicuously contradictory behavior of a polar, highly charged peptide passing through a nonpolar membrane set the stage for learning how Nature had gotten around the current "rules" of transport. As elaborated in our studies and discussed in this Account, the key strategy used in Nature rests in part on the ability of a molecule to change its properties as a function of microenvironment; such molecules need to be polarity chameleons, polar in a polar milieu and relatively nonpolar in a nonpolar environment. Because this research originated in part with the protein Tat and its basic peptide domain, Tat49-57, the field focused heavily on peptides, even limiting its nomenclature to names such as "cell-penetrating peptides," "cell-permeating peptides," "protein transduction domains," and "membrane translocating peptides." Starting in 1997, through a systematic reverse engineering approach, we established that the ability of Tat49-57 to enter cells is not a function of its peptide backbone, but rather a function of the number and spatial array of its guanidinium groups. These function-oriented studies enabled us and others to design more effective peptidic agents and to think beyond the confines of peptidic systems to new and even more effective nonpeptidic agents. Because the function of passage across a cell membrane is not limited to or even best achieved with the peptide backbone, we referred to these agents by their shared function, "cell-penetrating molecular transporters." The scope of this molecular approach to breaching biochemical barriers has expanded remarkably in the past 15 years: enabling or enhancing the delivery of a wide range of cargos into cells and across other biochemical barriers, creating new tools for research, imaging, and diagnostics, and introducing new therapies into clinical trials.

    View details for DOI 10.1021/ar4000554

    View details for Web of Science ID 000328797300021

  • Toward the ideal synthesis and transformative therapies: the roles of step economy and function oriented synthesis TETRAHEDRON Wender, P. A. 2013; 69 (36): 7529-7550
  • Highly potent, synthetically accessible prostratin analogs induce latent HIV expression in vitro and ex vivo PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Beans, E. J., Fournogerakis, D., Gauntlett, C., Heumann, L. V., Kramer, R., Marsden, M. D., Murray, D., Chun, T., Zack, J. A., Wender, P. A. 2013; 110 (29): 11698-11703

    Abstract

    Highly active antiretroviral therapy (HAART) decreases plasma viremia below the limits of detection in the majority of HIV-infected individuals, thus serving to slow disease progression. However, HAART targets only actively replicating virus and is unable to eliminate latently infected, resting CD4(+) T cells. Such infected cells are potentially capable of reinitiating virus replication upon cessation of HAART, thus leading to viral rebound. Agents that would eliminate these reservoirs, when used in combination with HAART, could thus provide a strategy for the eradication of HIV. Prostratin is a preclinical candidate that induces HIV expression from latently infected CD4(+) T cells, potentially leading to their elimination through a virus-induced cytopathic effect or host anti-HIV immunity. Here, we report the synthesis of a series of designed prostratin analogs and report in vitro and ex vivo studies of their activity relevant to induction of HIV expression. Members of this series are up to 100-fold more potent than the preclinical lead (prostratin) in binding to cell-free PKC, and in inducing HIV expression in a latently infected cell line and prostratin-like modulation of cell surface receptor expression in primary cells from HIV-negative donors. Significantly, selected members were also tested for HIV induction in resting CD4(+) T cells isolated from infected individuals receiving HAART and were found to exhibit potent induction activity. These more potent agents and by extension related tunable analogs now accessible through the studies described herein should facilitate research and preclinical advancement of this strategy for HIV/AIDS eradication.

    View details for DOI 10.1073/pnas.1302634110

    View details for Web of Science ID 000322086100023

    View details for PubMedID 23812750

  • Lead Diversification through a Prins-Driven Macrocyclization Strategy: Application to C13-Diversified Bryostatin Analogues SYNTHESIS-STUTTGART Wender, P. A., Billingsley, K. L. 2013; 45 (13): 1815-1824
  • Mechanistic and Computational Studies of Exocyclic Stereocontrol in the Synthesis of Bryostatin-like Cis-2,6-Disubstituted 4-Alkylidenetetrahydropyrans by Prins Cyclization JOURNAL OF ORGANIC CHEMISTRY Ogawa, Y., Painter, P. P., Tantillo, D. J., Wender, P. A. 2013; 78 (1): 104-115

    Abstract

    The Prins cyclization of syn-?-hydroxy allylsilanes and aldehydes gives cis-2,6-disubstituted 4-alkylidenetetrahydropyrans as sole products in excellent yields regardless of the aldehyde (R?) or syn-?-hydroxy allylsilane substituent (R') used. By reversing the R? and R' groups, complementary exocyclic stereocontrol can be achieved. When the anti-?-hydroxy allylsilanes are used, the Prins cyclization gives predominantly cis-2,6-disubstituted 4-alkylidenetetrahydropyrans, now with the opposite olefin geometry in excellent yield. The proposed reaction mechanism and the observed stereoselectivity for these processes are supported by DFT calculations.

    View details for DOI 10.1021/jo301953h

    View details for Web of Science ID 000313300000011

    View details for PubMedID 23121542

  • Designed, synthetically accessible bryostatin analogues potently induce activation of latent HIV reservoirs in vitro NATURE CHEMISTRY DeChristopher, B. A., Loy, B. A., Marsden, M. D., Schrier, A. J., Zack, J. A., Wender, P. A. 2012; 4 (9): 705-710

    Abstract

    Bryostatin is a unique lead in the development of potentially transformative therapies for cancer, Alzheimer's disease and the eradication of HIV/AIDS. However, the clinical use of bryostatin has been hampered by its limited supply, difficulties in accessing clinically relevant derivatives, and side effects. Here, we address these problems through the step-economical syntheses of seven members of a new family of designed bryostatin analogues using a highly convergent Prins-macrocyclization strategy. We also demonstrate for the first time that such analogues effectively induce latent HIV activation in vitro with potencies similar to or better than bryostatin. Significantly, these analogues are up to 1,000-fold more potent in inducing latent HIV expression than prostratin, the current clinical candidate for latent virus induction. This study provides the first demonstration that designed, synthetically accessible bryostatin analogues could serve as superior candidates for the eradication of HIV/AIDS through induction of latent viral reservoirs in conjunction with current antiretroviral therapy.

    View details for DOI 10.1038/NCHEM.1395

    View details for Web of Science ID 000308214200007

    View details for PubMedID 22914190

  • Effect of Histone Deacetylase Inhibitors on HIV Production in Latently Infected, Resting CD4(+) T Cells From Infected Individuals Receiving Effective Antiretroviral Therapy JOURNAL OF INFECTIOUS DISEASES Blazkova, J., Chun, T., Belay, B. W., Murray, D., Justement, J. S., Funk, E. K., Nelson, A., Hallahan, C. W., Moir, S., Wender, P. A., Fauci, A. S. 2012; 206 (5): 765-769

    Abstract

    Persistence of the latent viral reservoir has been recognized as a major obstacle to eradicating human immunodeficiency virus (HIV) in infected individuals receiving antiretroviral therapy. It has been suggested that histone deacetylase inhibitors (HDACis) may purge HIV in the latent viral reservoir. However, the effect of HDACis on the degree and extent of HIV expression in the latent viral reservoir has not been fully delineated. Here we demonstrate that HDACis do not induce HIV production in the latent viral reservoir of aviremic individuals. Therefore, alternative therapeutic strategies may be necessary to eliminate HIV in the latent viral reservoir.

    View details for DOI 10.1093/infdis/jis412

    View details for Web of Science ID 000307501800018

    View details for PubMedID 22732922

  • Designed guanidinium-rich amphipathic oligocarbonate molecular transporters complex, deliver and release siRNA in cells PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Geihe, E. I., Cooley, C. B., Simon, J. R., Kiesewetter, M. K., Edward, J. A., Hickerson, R. P., Kaspar, R. L., Hedrick, J. L., Waymouth, R. M., Wender, P. A. 2012; 109 (33): 13171-13176

    Abstract

    The polyanionic nature of oligonucleotides and their enzymatic degradation present challenges for the use of siRNA in research and therapy; among the most notable of these is clinically relevant delivery into cells. To address this problem, we designed and synthesized the first members of a new class of guanidinium-rich amphipathic oligocarbonates that noncovalently complex, deliver, and release siRNA in cells, resulting in robust knockdown of target protein synthesis in vitro as determined using a dual-reporter system. The organocatalytic oligomerization used to synthesize these co-oligomers is step-economical and broadly tunable, affording an exceptionally quick strategy to explore chemical space for optimal siRNA delivery in varied applications. The speed and versatility of this approach and the biodegradability of the designed agents make this an attractive strategy for biological tool development, imaging, diagnostics, and therapeutic applications.

    View details for DOI 10.1073/pnas.1211361109

    View details for Web of Science ID 000307807000017

    View details for PubMedID 22847412

  • A molecular method for the delivery of small molecules and proteins across the cell wall of algae using molecular transporters PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Hyman, J. M., Geihe, E. I., Trantow, B. M., Parvin, B., Wender, P. A. 2012; 109 (33): 13225-13230

    Abstract

    Interest in algae has significantly accelerated with the increasing recognition of their potentially unique role in medical, materials, energy, bioremediation, and synthetic biological research. However, the introduction of tools to study, control, or expand the inner-workings of algae has lagged behind. Here we describe a general molecular method based on guanidinium-rich molecular transporters (GR-MoTrs) for bringing small and large cargos into algal cells. Significantly, this method is shown to work in wild-type algae that have an intact cell wall. Developed using Chlamydomonas reinhardtii, this method is also successful with less studied algae including Neochloris oleoabundans and Scenedesmus dimorphus thus providing a new and versatile tool for algal research.

    View details for DOI 10.1073/pnas.1202509109

    View details for Web of Science ID 000307807000027

    View details for PubMedID 22847404

  • Bryostatin analogue-induced apoptosis in mantle cell lymphoma cell lines EXPERIMENTAL HEMATOLOGY Lopez-Campistrous, A., Song, X., Schrier, A. J., Wender, P. A., Dower, N. A., Stone, J. C. 2012; 40 (8): 646-656

    Abstract

    The anti-cancer effects of bryostatin-1, a potent diacylglycerol analogue, have traditionally been attributed to its action on protein kinase C. However, we previously documented apoptosis in a B non-Hodgkin lymphoma cell line involving diacylglycerol analogue stimulation of Ras guanyl-releasing protein, a Ras activator, and Bim, a proapoptotic Bcl-2 family protein. To further explore the role of Bim, we examined several Bim-deficient B non-Hodgkin lymphoma cells for their responses to pico, a synthetic bryostatin-1-like compound. The Bim(-) mantle cell lymphoma cell lines Jeko-1, Mino, Sp53, UPN1, and Z138 and the Bim(+) cell line Rec-1, as well as the Burkitt lymphoma cells lines BL2 (Bim(-)) and Daudi (Bim(+)), were examined for their response to pico using assays for proliferation and apoptosis as well as biochemical methods for Ras guanyl-releasing proteins and Bcl-2 family members. With the exception of UPN1, mantle cell lymphoma cell lines underwent pico-induced apoptosis, as did BL2. In some cases, hallmarks of apoptosis were substantially diminished in the presence of mitogen-activated protein kinase kinase inhibitors. Pico treatment generally led to increased expression of proapoptotic Bik, although the absolute levels of Bik varied considerably between cell lines. A pico-resistant variant of Z138 exhibited decreased Bik induction compared to parental Z138 cells. Pico also generally decreased expression of anti-apoptotic Bcl-XL and Mcl1. Although, these changes in Bcl-2 family members seem unlikely to fully account for the differential behavior of the cell lines, our demonstration of a potent apoptotic process in most cell lines derived from mantle cell lymphoma encourages a re-examination of diacylglycerol analogues in the treatment of this subset of B non-Hodgkin lymphoma cases.

    View details for DOI 10.1016/j.exphem.2012.03.002

    View details for Web of Science ID 000307319500005

    View details for PubMedID 22465296

  • Ligand Effects on Rates and Regioselectivities of Rh(I)-Catalyzed (5+2) Cycloadditions: A Computational Study of Cyclooctadiene and Dinaphthocyclooctatetraene as Ligands JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Xu, X., Liu, P., Lesser, A., Sirois, L. E., Wender, P. A., Houk, K. N. 2012; 134 (26): 11012-11025

    Abstract

    The first theoretical study on the effects of ligands on the mechanism, reactivities, and regioselectivities of Rh(I)-catalyzed (5 + 2) cycloadditions of vinylcyclopropanes (VCPs) and alkynes has been performed using density functional theory (DFT) calculations. Highly efficient and selective intermolecular (5 + 2) cycloadditions of VCPs and alkynes have been achieved recently using two novel rhodium catalysts, [Rh(dnCOT)](+)SbF(6)(-) and [Rh(COD)](+)SbF(6)(-), which provide superior reactivities and regioselectivities relative to that of the previously reported [Rh(CO)(2)Cl](2) catalyst. Computationally, the high reactivities of the dnCOT and COD ligands are attributed to the steric repulsions that destabilize the Rh-product complex, the catalyst resting state in the catalytic cycle. The regioselectivities of reactions with various alkynes and different Rh catalysts are investigated, and a predictive model is provided that describes substrate-substrate and ligand-substrate steric repulsions, electronic effects, and noncovalent ?/? and C-H/? interactions. In the reactions with dnCOT or COD ligands, the first new C-C bond is formed proximal to the bulky substituent on the alkyne to avoid ligand-substrate steric repulsions. This regioselectivity is reversed either by employing the smaller [Rh(CO)(2)Cl](2) catalyst to diminish the ligand-substrate repulsions or by using aryl alkynes, for which the ligand-substrate interactions become stabilizing due to ?/? and C-H/? dispersion interactions. Electron-withdrawing groups on the alkyne prefer to be proximal to the first new C-C bond to maximize metal-substrate back-bonding interactions. These steric, electronic, and dispersion effects can all be utilized in designing new ligands to provide regiochemical control over product formation with high selectivities. The computational studies reveal the potential of employing the dnCOT family of ligands to achieve unique regiochemical control due to the steric influences and dispersion interactions associated with the rigid aryl substituents on the ligand.

    View details for DOI 10.1021/ja3041724

    View details for Web of Science ID 000305863900049

    View details for PubMedID 22668243

  • Taxol-oligoarginine conjugates overcome drug resistance in-vitro in human ovarian carcinoma GYNECOLOGIC ONCOLOGY Wender, P. A., Galliher, W. C., Bhat, N. M., Pillow, T. H., Bieber, M. M., Teng, N. N. 2012; 126 (1): 118-123

    Abstract

    Multidrug resistance is the major cause of failure of many chemotherapeutic agents. While resistance can arise from several factors, it is often dominated by drug efflux mediated by P-glycoprotein (P-gp), a membrane-bound polysubstrate export pump expressed at high levels in resistant cells. While co-administration of pump inhibitors and a drug could suppress efflux, this two-drug strategy has not yet advanced to therapy. We recently demonstrated that the reversible attachment of a guanidinium-rich molecular transporter, polyarginine, to a drug provides a conjugate that overcomes efflux-based resistance in cells and animals. This study is to determine whether this strategy for overcoming resistance is effective against human disease.Tumor samples from ovarian cancer patients, both malignant ascites cells and dissociated solid tumor cells, were exposed to Taxol-oligoarginine conjugates designed to release free drug only after cell entry. Cell viability was determined via propidium-iodide uptake by flow cytometry. To analyze bystander effect, toxicity of the drug conjugates was also tested on peripheral blood leucocytes.Human ovarian carcinoma specimens resistant to Taxol in vitro demonstrated increased sensitivity to killing by all Taxol-transporter conjugates tested. These studies also show that the drug conjugates were not significantly more toxic to normal human peripheral blood leukocytes than Taxol.These studies with human tumor indicate that oligoarginine conjugates of known drugs can be used to overcome the efflux-based resistance to the drug, providing a strategy that could improve the treatment outcomes of patients with efflux-based drug-resistance.

    View details for DOI 10.1016/j.ygyno.2012.03.049

    View details for Web of Science ID 000305878400023

    View details for PubMedID 22484398

  • Rhodium Dinaphthocyclooctatetraene Complexes: Synthesis, Characterization and Catalytic Activity in [5+2] Cycloadditions ANGEWANDTE CHEMIE-INTERNATIONAL EDITION Wender, P. A., Lesser, A. B., Sirois, L. E. 2012; 51 (11): 2736-2740

    Abstract

    Rh COT in the act: a Ni(0)-catalyzed [2+2+2+2] cycloaddition provides a high-yielding, scalable synthesis of the ligand dinaphtho[a,e]cyclooctatetraene (dnCOT). dnCOT complexation with Rh(I) gives [Rh(dnCOT)(MeCN)(2)]SbF(6), an excellent catalyst for [5+2] cycloadditions of vinylcyclopropanes and ?-systems with impressive functional group compatibility.

    View details for DOI 10.1002/anie.201108270

    View details for Web of Science ID 000301173800038

    View details for PubMedID 22298411

  • Beyond Cell Penetrating Peptides: Designed Molecular Transporters. Drug discovery today. Technologies Wender, P. A., Cooley, C. B., Geihe, E. I. 2012; 9 (1): e49-e55

    Abstract

    Inspired originally by peptides that traverse biological barriers, research on molecular transporters has since identified the key structural requirements that govern cellular entry, leading to new, significantly more effective and more readily available agents. These new drug delivery systems enable or enhance cellular and tissue uptake, can be targeted, and provide numerous additional advantages of significance in imaging, diagnostics and therapy.

    View details for PubMedID 22712022

  • "Picolog," a Synthetically-Available Bryostatin Analog, Inhibits Growth of MYC-Induced Lymphoma In Vivo ONCOTARGET DeChristopher, B. A., Fan, A. C., Felsher, D. W., Wender, P. A. 2012; 3 (1): 58-66

    Abstract

    Bryostatin 1 is a naturally occurring complex macrolide with potent anti-neoplastic activity. However, its extremely low natural occurrence has impeded clinical advancement. We developed a strategy directed at the design of simplified and synthetically more accessible bryostatin analogs. Our lead analog, "picolog", can be step-economically produced. Picolog, compared to bryostatin, exhibited superior growth inhibition of MYC-induced lymphoma in vitro. A key mechanism of picolog's (and bryostatin's) activity is activation of PKC. A novel nano-immunoassay (NIA) revealed that picolog treatment increased phospho-MEK2 in the PKC pathway. Moreover, the inhibition of PKC abrogated picolog's activity. Finally, picolog was highly potent at 100 micrograms/kg and well tolerated at doses ranging from 100 micrograms/kg to 1 milligram/kg in vivo for the treatment of our aggressive model of MYC-induced lymphoma. We provide the first in vivo validation that the bryostatin analog, picolog, is a potential therapeutic agent for the treatment of cancer and other diseases.

    View details for Web of Science ID 000303914000009

    View details for PubMedID 22308267

  • Function oriented synthesis: preparation and initial biological evaluation of new A-ring-modified bryologs TETRAHEDRON Wender, P. A., Reuber, J. 2011; 67 (51): 9998-10005

    Abstract

    The synthesis and biological evaluation of the first members of a new series of designed bryostatin A-ring analogues (bryologs) are described. An advanced intermediate is produced that allows for step economical access to diverse analogs. The first of these analogues, bearing side chains of completely different polarities from alkyl to hydroxyl and carboxyl functionalities, were evaluated. All exhibit potent protein kinase C binding (54.7 to 2.4 nM) with affinities increasing with decreasing side chain polarity. This series of bryostatin analogues demonstrates that A ring surrogates can indeed be used for tuning pharmacophore and ADME characteristics as needed to improve bryolog function.

    View details for DOI 10.1016/j.tet.2011.09.058

    View details for Web of Science ID 000298027400024

  • Gateway synthesis of daphnane congeners and their protein kinase C affinities and cell-growth activities NATURE CHEMISTRY Wender, P. A., Buschmann, N., Cardin, N. B., Jones, L. R., Kan, C., Kee, J., Kowalski, J. A., Longcore, K. E. 2011; 3 (8): 615-619

    Abstract

    The daphnane diterpene orthoesters constitute a structurally fascinating family of natural products that exhibit a remarkable range of potent biological activities. Although partial activity information is available for some natural daphnanes, little information exists for non-natural congeners or on how changes in structure affect mode of action, function, potency or selectivity. A gateway strategy designed to provide general synthetic access to natural and non-natural daphnanes is described and utilized in the synthesis of two novel members of this class. In this study, a commercially available tartrate derivative was elaborated through a key late-stage diversification intermediate into B-ring yuanhuapin analogues to initiate exploration of the structure-function relationships of this class. Protein kinase C was identified as a cellular target for these agents, and their activity against human lung and leukaemia cell lines was evaluated. The natural product and a novel non-natural analogue exhibited significant potency, but the epimeric epoxide was essentially inactive.

    View details for DOI 10.1038/NCHEM.1074

    View details for Web of Science ID 000292999100014

    View details for PubMedID 21778981

  • Total Synthesis of Bryostatin 9 JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Wender, P. A., Schrier, A. J. 2011; 133 (24): 9228-9231

    Abstract

    The total synthesis of bryostatin 9 was accomplished using a uniquely step-economical and convergent Prins-driven macrocyclization strategy. At 25 linear and 42 total steps, this is currently the most concise and convergent synthesis of a potent bryostatin.

    View details for DOI 10.1021/ja203034k

    View details for Web of Science ID 000291915100025

    View details for PubMedID 21618969

  • Design, synthesis, and evaluation of potent bryostatin analogs that modulate PKC translocation selectivity PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Wender, P. A., Baryza, J. L., Brenner, S. E., DeChristopher, B. A., Loy, B. A., Schrier, A. J., Verma, V. A. 2011; 108 (17): 6721-6726

    Abstract

    Modern methods for the identification of therapeutic leads include chemical or virtual screening of compound libraries. Nature's library represents a vast and diverse source of leads, often exhibiting exquisite biological activities. However, the advancement of natural product leads into the clinic is often impeded by their scarcity, complexity, and nonoptimal properties or efficacy as well as the challenges associated with their synthesis or modification. Function-oriented synthesis represents a strategy to address these issues through the design of simpler and therefore synthetically more accessible analogs that incorporate the activity-determining features of the natural product leads. This study illustrates the application of this strategy to the design and synthesis of functional analogs of the bryostatin marine natural products. It is specifically directed at exploring the activity-determining role of bryostatin A-ring functionality on PKC affinity and selectivity. The resultant functional analogs, which were prepared by a flexible, modular synthetic strategy, exhibit excellent affinity to PKC and differential isoform selectivity. These and related studies provide the basic information needed for the design of simplified and thus synthetically more accessible functional analogs that target PKC isoforms, major targets of therapeutic interest.

    View details for DOI 10.1073/pnas.1015270108

    View details for Web of Science ID 000289888500012

    View details for PubMedID 21415363

  • Translating Nature's Library: The Bryostatins and Function-Oriented Synthesis ISRAEL JOURNAL OF CHEMISTRY Wender, P. A., Loy, B. A., Schrier, A. J. 2011; 51 (3-4): 453-472
  • Electronic and Steric Control of Regioselectivities in Rh(I)-Catalyzed (5+2) Cycloadditions: Experiment and Theory JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Liu, P., Sirois, L. E., Cheong, P. H., Yu, Z., Hartung, I. V., Rieck, H., Wender, P. A., Houk, K. N. 2010; 132 (29): 10127-10135

    Abstract

    The first studies on the regioselectivity of Rh(I)-catalyzed (5 + 2) cycloadditions between vinylcyclopropanes (VCPs) and alkynes have been conducted experimentally and analyzed using density functional theory (DFT). The previously unexplored regiochemical consequences for this catalytic, intermolecular cycloaddition were determined by studying the reactions of several substituted VCPs with a range of unsymmetrical alkynes. Experimental trends were identified, and a predictive model was established. VCPs with terminal substitution on the alkene reacted with high regioselectivity (>20:1), as predicted by a theoretical model in which bulkier alkyne substituents prefer to be distal to the forming C-C bond to avoid steric repulsions. VCPs with substitution at the internal position of the alkene reacted with variable regioselectivity (ranging from >20:1 to a reversed 1:2.3), suggesting a refined model in which electron-withdrawing substituents on the alkyne decrease or reverse sterically controlled selectivity by stabilizing the transition state in which the substituent is proximal to the forming C-C bond.

    View details for DOI 10.1021/ja103253d

    View details for Web of Science ID 000280227700048

    View details for PubMedID 20586494

  • Highly Efficient, Facile, Room Temperature Intermolecular [5+2] Cycloadditions Catalyzed by Cationic Rhodium(I): One Step to Cycloheptenes and Their Libraries ORGANIC LETTERS Wender, P. A., Sirois, L. E., Stemmler, R. T., Williams, T. J. 2010; 12 (7): 1604-1607

    Abstract

    A cationic rhodium(I) complex--[(C(10)H(8))Rh(cod)](+) SbF(6)(-)--catalyzes the remarkably efficient intermolecular [5 + 2] cycloaddition of vinylcyclopropanes (VCPs) and various alkynes, providing cycloheptene cycloadducts in excellent yields in minutes at room temperature. The efficacy and selectivity of this catalyst are also shown in a novel diversification strategy, affording a cycloadduct library in one step from nine commercially available components.

    View details for DOI 10.1021/ol100337m

    View details for Web of Science ID 000275885400058

    View details for PubMedID 20196579

  • Special delivery: One-step oligomerization of oligocarbonate molecular transporters and biological evaluation of uptake and delivery Cooley, C. B., Trantow, B. M., Kiesewetter, M. K., Nederberg, F., Hedrick, J. L., Waymouth, R. M., Wender, P. A. AMER CHEMICAL SOC. 2010
  • A Metal-Catalyzed Intermolecular [5+2] Cycloaddition/Nazarov Cyclization Sequence and Cascade JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Wender, P. A., Stemmler, R. T., Sirois, L. E. 2010; 132 (8): 2532-?

    Abstract

    The bicyclo[5.3.0]decane skeleton is one of the most commonly encountered bicyclic subunits in nature and the core scaffold of a wide range of targets of structural, biological, and therapeutic importance. Prompted by the interest in such structures, we report the first studies of metal-catalyzed [5+2] cycloadditions of vinylcyclopropanes (VCPs) and enynones. The resultant efficiently formed dienone cycloadducts serve as substrates for subsequent Nazarov cyclizations and as intermediates for single-operation [5+2]/Nazarov serial reactions and catalytic cascades. In many cases the one-flask process can be carried out in shorter reaction times and with comparable or superior yields to the two-flask procedure. Significantly, a single catalyst can be used to mediate both transformations. These [5+2]/Nazarov reaction sequences and cascades collectively provide strategically novel and facile access to the bicyclo[5.3.0]decane skeleton from simple and readily available components.

    View details for DOI 10.1021/ja910696x

    View details for Web of Science ID 000275117900021

    View details for PubMedID 20141136

  • The Diene Effect: The Design, Development, and Mechanistic Investigation of Metal-Catalyzed Diene-yne, Diene-ene, and Diene-allene [2+2+1] Cycloaddition Reactions EUROPEAN JOURNAL OF ORGANIC CHEMISTRY Croatt, M. P., Wender, P. A. 2010: 19-32
  • Apoptolidins E and F, New Glycosylated Macrolactones Isolated from Nocardiopsis sp. ORGANIC LETTERS Wender, P. A., Longcore, K. E. 2009; 11 (23): 5474-5477

    Abstract

    Two new glycosylated macrolactones, apoptolidins E (5) and F (6), were isolated from fermentation of the actinomycete Nocardiopsis sp. and their structures assigned. Lacking the C16 and C20 oxygens of apoptolidin A (1), these macrolides are also the first members of this family to display a 4-O-methyl-l-rhamnose at C9 rather than a 6-deoxy-4-O-methyl-l-glucose.

    View details for DOI 10.1021/ol902308v

    View details for Web of Science ID 000272038200029

    View details for PubMedID 19943700

  • Oligocarbonate Molecular Transporters: Oligomerization-Based Syntheses and Cell-Penetrating Studies JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Cooley, C. B., Trantow, B. M., Nederberg, F., Kiesewetter, M. K., Hedrick, J. L., Waymouth, R. M., Wender, P. A. 2009; 131 (45): 16401-?

    Abstract

    A new family of guanidinium-rich molecular transporters featuring a novel oligocarbonate backbone with 1,7-side chain spacing is described. Conjugates can be rapidly assembled irrespective of length in a one-step oligomerization strategy that can proceed with concomitant introduction of probes (or by analogy drugs). The new transporters exhibit excellent cellular entry as determined by flow cytometry and fluorescence microscopy, and the functionality of their drug delivery capabilities was confirmed by the delivery of the bioluminescent small molecule probe luciferin and turnover by its intracellular target enzyme.

    View details for DOI 10.1021/ja907363k

    View details for Web of Science ID 000271723000030

    View details for PubMedID 19860416

  • Prolonging microtubule dysruption enhances the immunogenicity of chronic lymphocytic leukaemia cells CLINICAL AND EXPERIMENTAL IMMUNOLOGY Shaha, S. P., Tomic, J., Shi, Y., Pham, T., Mero, P., White, D., He, L., Baryza, J. L., Wender, P. A., Booth, J. W., Spaner, D. E. 2009; 158 (2): 186-198

    Abstract

    Cytotoxic chemotherapies do not usually mediate the expression of an immunogenic gene programme in tumours, despite activating many of the signalling pathways employed by highly immunogenic cells. Concomitant use of agents that modulate and complement stress-signalling pathways activated by chemotherapeutic agents may then enhance the immunogenicity of cancer cells, increase their susceptibility to T cell-mediated controls and lead to higher clinical remission rates. Consistent with this hypothesis, the microtubule inhibitor, vincristine, caused chronic lymphocytic leukaemia (CLL) cells to die rapidly, without increasing their immunogenicity. Protein kinase C (PKC) agonists (such as bryostatin) delayed the death of vincristine-treated CLL cells and made them highly immunogenic, with increased stimulatory abilities in mixed lymphocyte responses, production of proinflammatory cytokines, expression of co-stimulatory molecules and activation of c-Jun N-terminal kinase (JNK), p38 and nuclear factor kappa B (NF-kappaB) signalling pathways. This phenotype was similar to the result of activating CLL cells through Toll-like receptors (TLRs), which communicate 'danger' signals from infectious pathogens. Use of PKC agonists and microtubule inhibitors to mimic TLR-signalling, and increase the immunogenicity of CLL cells, has implications for the design of chemo-immunotherapeutic strategies.

    View details for DOI 10.1111/j.1365-2249.2009.04003.x

    View details for Web of Science ID 000270397000004

    View details for PubMedID 19737143

  • Rhodium(I)-Catalyzed [2+2], [2+2+2], and [2+2+2+2] Cycloadditions of Dienes or Alkynes with a Bis-ene ORGANOMETALLICS Wender, P. A., Croatt, M. P., Kuehn, B. 2009; 28 (20): 5841-5844

    View details for DOI 10.1021/om9007373

    View details for Web of Science ID 000270789200002

  • An Approach to the Site-Selective Diversification of Apoptolidin A with Peptide-Based Catalysts JOURNAL OF NATURAL PRODUCTS Lewis, C. A., Longcore, K. E., Miller, S. J., Wender, P. A. 2009; 72 (10): 1864-1869

    Abstract

    We report the application of peptide-based catalysts to the site-selective modification of apoptolidin A (1), an agent that displays remarkable selectivity for inducing apoptosis in E1A-transformed cell lines. Key to the approach was the development of an assay suitable for the screening of dozens of catalysts in parallel reactions that could be conducted using only microgram quantities of the starting material. Employing this assay, catalysts (e.g., 11 and ent-11) were identified that afforded unique product distributions, distinct from the product mixtures produced when a simple catalyst (N,N-dimethyl-4-aminopyridine (10)) was employed. Preparative reactions were then carried out with the preferred catalysts so that unique, homogeneous apoptolidin analogues could be isolated and characterized. From these studies, three new apoptolidin analogues were obtained (12-14), each differing from the other in either the location of acyl group substituents or the number of acetate groups appended to the natural product scaffold. Biological evaluation of the new apoptolidin analogues was then conducted using growth inhibition assays based on the H292 human lung carcinoma cell line. The new analogues exhibited activities comparable to apoptolidin A.

    View details for DOI 10.1021/np9004932

    View details for Web of Science ID 000271950400022

    View details for PubMedID 19769383

  • Synthesis at the molecular frontier NATURE Wender, P. A., Miller, B. L. 2009; 460 (7252): 197-201

    View details for DOI 10.1038/460197a

    View details for Web of Science ID 000267761000029

    View details for PubMedID 19587760

  • Cyclocarboamination of Alkynes with Aziridines: Synthesis of 2,3-Dihydropyrroles by a Catalyzed Formal [3+2] Cycloaddition JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Wender, P. A., Strand, D. 2009; 131 (22): 7528-?

    Abstract

    An efficient cyclocarboamination reaction of nonactivated alkynes with aziridines, catalyzed by Lewis or Bronsted acids, to form 2,3-dihydropyrroles through a formal [3+2] cycloaddition, is described. The reaction provides a wide range of polysubstituted dihydropyrroles in a highly regioselective manner, is scalable, proceeds under mild reaction conditions, and uses low catalyst loadings.

    View details for DOI 10.1021/ja901799s

    View details for Web of Science ID 000267177900025

    View details for PubMedID 19489638

  • A cellular model of Alzheimer's disease therapeutic efficacy: PKC activation reverses A beta-induced biomarker abnormality on cultured fibroblasts NEUROBIOLOGY OF DISEASE Khan, T. K., Nelson, T. J., Verma, V. A., Wender, P. A., Alkon, D. L. 2009; 34 (2): 332-339

    Abstract

    PKC signaling is critical for the non-toxic degradation of amyloid precursor protein (APP) and inhibition of GSK3beta, which controls phosphorylation of tau protein in Alzheimer's disease (AD). Thus the misregulation of PKC signaling could contribute to the origins of AD. Bryostatin, a potent PKC modulator, has the potential to ameliorate both the neurodegeneration and the recent memory loss associated with AD. As reported herein bryostatin and a potent synthetic analog (picolog) are found to cause stimulation of non-amyloidogenic pathways by increasing alpha-secretase activity and thus lowering the amount of toxic Abeta produced. Both bryostatin and picolog increased the secretion of the alpha-secretase product (s-APP-alpha) of APP at sub-nanomolar to nanomolar concentrations. A peripheral AD-Biomarker has previously been autopsy-validated. This Biomarker, based on bradykinin-induced differential phosphorylation of Erk1 and Erk2, has been used here to test the therapeutic efficacy both for bryostatin and picolog. Both of these PKC activators are then shown to convert the AD Erk1/2 phenotype of fibroblasts into the phenotype of "normal" control skin fibroblasts. This conversion occurred for both the abnormal Erk1/2 phenotype induced by application of Abeta(1-42) to the fibroblasts or the phenotype observed for fibroblasts of AD patients. The Abeta(1-42)-induction, and PKC modulator reversal of the AD Erk1/2 biomarker phenotype demonstrate the AD-Biomarker's potential to monitor both disease progression and treatment response. Additionally, this first demonstration of the therapeutic potential in AD of a synthetically accessible bryostatin analog warrants further preclinical advancement.

    View details for DOI 10.1016/j.nbd.2009.02.003

    View details for Web of Science ID 000265869400014

    View details for PubMedID 19233276

  • The Synthesis of Highly Substituted Cyclooctatetraene Scaffolds by Metal-Catalyzed [2+2+2+2] Cycloadditions: Studies on Regioselectivity, Dynamic Properties, and Metal Chelation ANGEWANDTE CHEMIE-INTERNATIONAL EDITION Wender, P. A., Christy, J. P., Lesser, A. B., Gieseler, M. T. 2009; 48 (41): 7687-7690

    View details for DOI 10.1002/anie.200903859

    View details for Web of Science ID 000270436900041

    View details for PubMedID 19739178

  • A proapoptotic signaling pathway involving RasGRP, Erk, and Bim in B cells EXPERIMENTAL HEMATOLOGY Stang, S. L., Lopez-Campistrous, A., Song, X., Dower, N. A., Blumberg, P. M., Wender, P. A., Stone, J. C. 2009; 37 (1): 122-134

    Abstract

    Bryostatin-1 and related diacylglycerol (DAG) analogues activate RasGRPs in lymphocytes, thereby activating Ras and mimicking some aspects of immune receptor signaling. To define the role of RasGRPs in lymphocyte apoptosis and to identify potential therapeutic uses for DAG analogues in lymphocyte disorders, we characterized the response of lymphoma-derived cell lines to DAG analogues.Human lymphoma-derived B cell lines and mouse primary B cells were treated with bryostatin-1 or its synthetic analogue "pico." Ras signaling partners and Bcl-2 family members were studied with biochemical assays. Cellular responses were monitored using growth and apoptosis assays.Stimulation of B cells with DAG analogues results in activation of protein kinase C/RasGRP-Ras-Raf-Mek-Erk signaling and phosphorylation of the proapoptotic BH3-only protein Bim. In vitro, Bim is phosphorylated by Erk on sites previously associated with increased apoptotic activity. In Toledo B cells derived from a non-Hodgkin's lymphoma (B-NHL), DAG analogue stimulation leads to extensive apoptosis. Apoptosis can be suppressed by either downregulation of Bim or overexpression of Bcl-2. It is associated with the formation of Bak-Bax complexes and increased mitochondrial membrane permeability. Toledo B-NHL cell apoptosis shows a striking dependence on sustained signaling.In B cells, Erk activation leads directly to phosphorylation of Bim on sites associated with activation of Bim. In Toledo B-NHL cells, the dependence of apoptosis on sustained signaling suggests that Bcl-2 family members could interpret signal duration, an important determinant of B cell receptor-mediated negative selection. Certain cases of B-NHL might respond to DAG analogue treatment by the mechanism outlined here.

    View details for DOI 10.1016/j.exphem.2008.09.008

    View details for Web of Science ID 000262216400014

    View details for PubMedID 19100522

  • Function-oriented synthesis: Biological evaluation of laulimalide analogues derived from a last step cross metathesis diversification strategy MOLECULAR PHARMACEUTICS Mooberry, S. L., Hilinski, M. K., Clark, E. A., Wender, P. A. 2008; 5 (5): 829-838

    Abstract

    Laulimalide is a potent microtubule stabilizing agent and a promising anticancer therapeutic lead. The identification of stable, efficacious and accessible analogues is critical to clinically exploiting this novel lead. To determine which structural features of laulimalide are required for beneficial function and thus for accessing superior clinical candidates, a series of side chain analogues were prepared through a last step cross metathesis diversification strategy and their biological activities were evaluated. Five analogues, differing in potency from 233 nM to 7.9 muM, effectively inhibit cancer cell proliferation. Like laulimalide, they retain activity against multidrug resistant cells, stabilize microtubules and cause the formation of aberrant mitotic spindles, mitotic accumulation, Bcl-2 phosphorylation and initiation of apoptosis. Structural modifications in the C 23-C 27 dihydropyran side chain can be made without changing the overall mechanism of action, but it is clear that this subunit has more than a bystander role.

    View details for DOI 10.1021/mp800043n

    View details for Web of Science ID 000259859500014

    View details for PubMedID 18662015

  • Overcoming multidrug resistance of small-molecule therapeutics through conjugation with releasable octaarginine transporters PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Dubikovskaya, E. A., Thorne, S. H., Pillow, T. H., Contag, C. H., Wender, P. A. 2008; 105 (34): 12128-12133

    Abstract

    Many cancer therapeutic agents elicit resistance that renders them ineffective and often produces cross-resistance to other drugs. One of the most common mechanisms of resistance involves P-glycoprotein (Pgp)-mediated drug efflux. To address this problem, new agents have been sought that are less prone to inducing resistance and less likely to serve as substrates for Pgp efflux. An alternative to this approach is to deliver established agents as molecular transporter conjugates into cells through a mechanism that circumvents Pgp-mediated efflux and allows for release of free drug only after cell entry. Here we report that the widely used chemotherapeutic agent Taxol, ineffective against Taxol-resistant human ovarian cancer cell lines, can be incorporated into a releasable octaarginine conjugate that is effective against the same Taxol-resistant cell lines. It is significant that the ability of the Taxol conjugates to overcome Taxol resistance is observed both in cell culture and in animal models of ovarian cancer. The generality and mechanistic basis for this effect were also explored with coelenterazine, a Pgp substrate. Although coelenterazine itself does not enter cells because of Pgp efflux, its octaarginine conjugate does so readily. This approach shows generality for overcoming the multidrug resistance elicited by small-molecule cancer chemotherapeutics and could improve the prognosis for many patients with cancer and fundamentally alter search strategies for novel therapeutic agents that are effective against resistant disease.

    View details for DOI 10.1073/pnas.0805374105

    View details for Web of Science ID 000258905700008

    View details for PubMedID 18713866

  • The design, synthesis, and evaluation of C7 diversified bryostatin analogs reveals a hot spot for PKC affinity ORGANIC LETTERS Wender, P. A., Verma, V. A. 2008; 10 (15): 3331-3334

    Abstract

    The first series of systematically varied C7-functionalized bryostatin analogs (12 members in all) have been synthesized through an efficient and convergent route. A new hotspot for PKC affinity, not present in the natural products, has been discovered, allowing for affinity control and potentially for selective regulation of PKC isozymes. Several analogs exhibit single-digit nanomolar affinity to PKC and display superior activity compared to bryostatin against the leukemia cell line K562.

    View details for DOI 10.1021/ol801235h

    View details for Web of Science ID 000257955100041

    View details for PubMedID 18588309

  • Single-molecule motions of oligoarginine transporter conjugates on the plasma membrane of Chinese hamster ovary cells JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Lee, H., Dubikovskaya, E. A., Hwang, H., Semyonov, A. N., Wang, H., Jones, L. R., TWIEG, R. J., Moerner, W. E., Wender, P. A. 2008; 130 (29): 9364-9370

    Abstract

    To explore the real-time dynamic behavior of molecular transporters of the cell-penetrating-peptide (CPP) type on a biological membrane, single fluorescently labeled oligoarginine conjugates were imaged interacting with the plasma membrane of Chinese hamster ovary (CHO) cells. The diffusional motion on the membrane, characterized by single-molecule diffusion coefficient and residence time (tau R), defined as the time from the initial appearance of a single-molecule spot on the membrane (from the solution) to the time the single molecule disappears from the imaging focal plane, was observed for a fluorophore-labeled octaarginine (a model guanidinium-rich CPP) and compared with the corresponding values observed for a tetraarginine conjugate (negative control), a lipid analogue, and a fluorescently labeled protein conjugate (transferrin-Alexa594) known to enter the cell through endocytosis. Imaging of the oligoarginine conjugates was enabled by the use of a new high-contrast fluorophore in the dicyanomethylenedihydrofuran family, which brightens upon interaction with the membrane at normal oxygen concentrations. Taken as a whole, the motions of the octaarginine conjugate single molecules are highly heterogeneous and cannot be described as Brownian motion with a single diffusion coefficient. The observed behavior is also different from that of lipids, known to penetrate cellular membranes through passive diffusion, conventionally involving lateral diffusion followed by membrane bilayer flip-flop. Furthermore, while the octaarginine conjugate behavior shares some common features with transferrin uptake (endocytotic) processes, the two systems also exhibit dissimilar traits when diffusional motions and residence times of single constructs are compared. Additionally, pretreatment of cells with cytochalasin D, a known actin filament disruptor, produces no significant effect, which further rules out unimodal endocytosis as the mechanism of uptake. Also, the involvement of membrane potential in octaarginine-membrane interaction is supported by significant changes in the motion with high [K(+)] treatment. In sum, this first study of single transporter motion on the membrane of a living cell indicates that the mode by which the octaarginine transporter penetrates the cell membrane appears to either be a multimechanism uptake process or a mechanism different from unimodal passive diffusion or endocytosis.

    View details for DOI 10.1021/ja710798b

    View details for Web of Science ID 000257796500048

    View details for PubMedID 18578528

  • Efficient synthetic access to a new family of highly potent bryostatin analogues via a prins-driven macrocyclization strategy JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Wender, P. A., DeChristopher, B. A., Schrier, A. J. 2008; 130 (21): 6658-?

    Abstract

    The step-economical synthesis of a new class of bryostatin analogues that contain the complete oxycarbocyclic core ring system of the bryostatin natural products is reported. These agents are convergently assembled via a highly efficient, functional-group-tolerant, and stereoselective Prins-driven macrocyclization. These tetrahydropyranyl B-ring analogues are among our most potent and efficacious analogues to date, exhibiting nanomolar and picomolar activities in protein kinase C affinity assays as well as in cellular antiproliferation assays.

    View details for DOI 10.1021/ja8015632

    View details for Web of Science ID 000256158200003

    View details for PubMedID 18452292

  • Practical synthesis of prostratin, DPP, and their analogs, adjuvant leads against latent HIV SCIENCE Wender, P. A., Kee, J., Warrington, J. M. 2008; 320 (5876): 649-652

    Abstract

    Although antiretroviral therapies have been effective in decreasing active viral loads in AIDS patients, the persistence of latent viral reservoirs prevents eradication of the virus. Prostratin and DPP (12-deoxyphorbol-13-phenylacetate) activate the latent virus and thus represent promising adjuvants for antiviral therapy. Their limited supply and the challenges of accessing related structures have, however, impeded therapeutic development and the search for clinically superior analogs. Here we report a practical synthesis of prostratin and DPP starting from phorbol or crotophorbolone, agents readily available from renewable sources, including a biodiesel candidate. This synthesis reliably supplies gram quantities of the therapeutically promising natural products, hitherto available only in low and variable amounts from natural sources, and opens access to a variety of new analogs.

    View details for DOI 10.1126/science.1154690

    View details for Web of Science ID 000255454300041

    View details for PubMedID 18451298

  • ORGN 694-Theoretical studies on rhodium(I) catalyzed (5+2) cycloadditions Liu, P., Cheong, P. H., Yu, Z., Legault, C. Y., Wender, P. A., Houk, K. N. AMER CHEMICAL SOC. 2008
  • The design of guanidinium-rich transporters and their internalization mechanisms ADVANCED DRUG DELIVERY REVIEWS Wender, P. A., Galliher, W. C., Goun, E. A., Jones, L. R., Pillow, T. H. 2008; 60 (4-5): 452-472

    Abstract

    The ability of a drug or probe to cross a biological barrier has historically been viewed to be a function of its intrinsic physical properties. This view has largely restricted drug design and selection to agents within a narrow log P range. Molecular transporters offer a strategy to circumvent these restrictions. In the case of guanidinium-rich transporters (GRTs), a typically highly water-soluble conjugate is found to readily pass through the non-polar membrane of a cell and for some across tissue barriers. This activity opens a field of opportunities for the use of GRTs to enable delivery of polar and non-polar drugs or probes as well as to enhance uptake of those of intermediate polarity. The field of transporter enabled or enhanced uptake has grown dramatically in the last decade. Some GRT drug conjugates have been advanced into clinical trials. This review will provide an overview of recent work pertinent to the design and mechanism of uptake of GRTs.

    View details for DOI 10.1016/j.addr.2007.10.016

    View details for Web of Science ID 000254068000003

    View details for PubMedID 18164781

  • Origins of differences in reactivities of alkenes, alkynes, and allenes in [Rh(CO)(2)CI](2)-catalyzed (5+2) cycloaddition reactions with vinylcyclopropanes JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Yu, Z., Cheong, P. H., Liu, P., Legault, C. Y., Wender, P. A., Houk, K. N. 2008; 130 (8): 2378-2379

    View details for DOI 10.1021/ja076444d

    View details for Web of Science ID 000253400900003

    View details for PubMedID 18251468

  • Substituent effects, reactant preorganization, and ligand exchange control the reactivity in Rh-I-catalyzed (5+2) cycloadditions between vinylcyclopropanes and alkynes ANGEWANDTE CHEMIE-INTERNATIONAL EDITION Liu, P., Cheong, P. H., Yu, Z., Wender, P. A., Houk, K. N. 2008; 47 (21): 3939-3941

    View details for DOI 10.1002/anie.200800420

    View details for Web of Science ID 000255994700014

    View details for PubMedID 18412215

  • Function-oriented synthesis, step economy, and drug design ACCOUNTS OF CHEMICAL RESEARCH Wender, P. A., Verma, V. A., Paxton, T. J., Pillow, T. H. 2008; 41 (1): 40-49

    Abstract

    This Account provides an overview and examples of function-oriented synthesis (FOS) and its increasingly important role in producing therapeutic leads that can be made in a step-economical fashion. Biologically active natural product leads often suffer from several deficiencies. Many are scarce or difficult to obtain from natural sources. Often, they are highly complex molecules and thus not amenable to a practical synthesis that would impact supply. Most are not optimally suitable for human therapeutic use. The central principle of FOS is that the function of a biologically active lead structure can be recapitulated, tuned, or greatly enhanced with simpler scaffolds designed for ease of synthesis and also synthetic innovation. This approach can provide practical access to new (designed) structures with novel activities while at the same time allowing for synthetic innovation by target design. This FOS approach has been applied to a number of therapeutically important natural product leads. For example, bryostatin is a unique natural product anticancer lead that restores apoptosis in cancer cells, reverses multidrug resistance, and bolsters the immune system. Remarkably, it also improves cognition and memory in animals. We have designed and synthesized simplified analogs of bryostatin that can be made in a practical fashion (pilot scale) and are superior to bryostatin in numerous assays including growth inhibition in a variety of human cancer cell lines and in animal models. Laulimalide is another exciting anticancer lead that stabilizes microtubules, like paclitaxel, but unlike paclitaxel, it is effective against multidrug-resistant cell lines. Laulimalide suffers from availability and stability problems, issues that have been addressed using FOS through the design and synthesis of stable and efficacious laulimalide analogs. Another FOS program has been directed at the design and synthesis of drug delivery systems for enabling or enhancing the uptake of drugs or drug candidates into cells and tissue. We have generated improved transporters that can deliver agents in a superior fashion compared with naturally occurring cell-penetrating peptides and that can be synthesized in a practical and step-economical fashion. The use of FOS has allowed for the translation of exciting, biologically active natural product leads into simplified analogs with superior function. This approach enables the development of synthetically innovative strategies while targeting therapeutically novel structures.

    View details for DOI 10.1021/ar700155p

    View details for Web of Science ID 000252419500006

    View details for PubMedID 18159936

  • Nickel(0)-catalyzed [2+2+2+2] cycloadditions of terminal diynes for the synthesis of substituted cyclooctatetraenes JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Wender, P. A., Christy, J. P. 2007; 129 (44): 13402-?

    View details for DOI 10.1021/ja0763044

    View details for Web of Science ID 000250819200022

    View details for PubMedID 17929819

  • N-Alkoxyimidazolylidene transition-metal complexes: Application to [5+2] and [4+2] cycloaddition reactions ORGANOMETALLICS Gomez, F. J., Kamber, N. E., Deschamps, N. M., Cole, A. P., Wender, P. A., Waymouth, R. M. 2007; 26 (18): 4541-4545

    View details for DOI 10.1021/om700493y

    View details for Web of Science ID 000248865600026

  • A computationally designed Rh(I)-catalyzed two-component [5+2+1] cycloaddition of ene-vinylcyclopropanes and CO for the synthesis of cyclooctenones JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Wang, Y., Wang, J., Su, J., Huang, F., Jiao, L., Liang, Y., Yang, D., Zhang, S., Wender, P. A., Yu, Z. 2007; 129 (33): 10060-?

    View details for DOI 10.1021/ja072505w

    View details for Web of Science ID 000248896400008

    View details for PubMedID 17655302

  • Real-time analysis of uptake and bioactivatable cleavage of luciferin-transporter conjugates in transgenic reporter mice PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Wender, P. A., Goun, E. A., Jones, L. R., Pillow, T. H., Rothbard, J. B., Shinde, R., Contag, C. H. 2007; 104 (25): 10340-10345

    Abstract

    Many therapeutic leads fail to advance clinically because of bioavailability, selectivity, and formulation problems. Molecular transporters can be used to address these problems. Molecular transporter conjugates of otherwise poorly soluble or poorly bioavailable drugs or probes exhibit excellent solubility in water and biological fluids and at the same time an enhanced ability to enter tissues and cells and with modification to do so selectively. For many conjugates, however, it is necessary to release the drug/probe cargo from the transporter after uptake to achieve activity. Here, we describe an imaging method that provides quantification of transporter conjugate uptake and cargo release in real-time in animal models. This method uses transgenic (luciferase) reporter mice and whole-body imaging, allowing noninvasive quantification of transporter conjugate uptake and probe (luciferin) release in real time. This process effectively emulates drug-conjugate delivery, drug release, and drug turnover by an intracellular target, providing a facile method to evaluate comparative uptake of new transporters and efficacy and selectivity of linker release as required for fundamental studies and therapeutic applications.

    View details for DOI 10.1073/pnas.0703919104

    View details for Web of Science ID 000247500000010

    View details for PubMedID 17563383

  • Function-oriented synthesis: Studies aimed at the synthesis and mode of action of 1 alpha-alkyldaphnane analogues ORGANIC LETTERS Wender, P. A., D'Angelo, N., Elitzin, V. I., Ernst, M., Jackson-Ugueto, E. E., Kowalski, J. A., McKendry, S., Rehfeuter, M., Sun, R., Voigtlaender, D. 2007; 9 (9): 1829-1832

    Abstract

    [reaction: see text] An efficient synthetic route to the ABC tricyclic core of 1alpha-alkyldaphnanes has been developed. The conformational bias imparted by the C6-C9 oxo-bridge of BC-ring system 12 was used to elaborate the ABC-ring system precursor including the introduction of the beta-C5 hydroxyl group. A completely diastereoselective palladium-catalyzed enyne cyclization was then employed to establish the A-ring with a C1 appendage.

    View details for DOI 10.1021/ol0705649

    View details for Web of Science ID 000245799200054

    View details for PubMedID 17408281

  • Isolation, structure determination, and anti-cancer activity of apoptolidin D ORGANIC LETTERS Wender, P. A., Longcore, K. E. 2007; 9 (4): 691-694

    Abstract

    The isolation, characterization, and preliminary biological activity of apoptolidin D, a new apoptolidin that exhibits anti-proliferative activity against H292 human lung carcinoma cells at nanomolar concentrations, are reported. Its equilibration with isoapoptolidin D and characterization of the latter are also described. [structure: see text].

    View details for DOI 10.1021/ol0630245

    View details for Web of Science ID 000244039800037

    View details for PubMedID 17286376

  • Cyclopentadienone synthesis by rhodium(I)-catalyzed [3+2] cycloaddition reactions of cyclopropenones and alkynes JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Wender, P. A., Paxton, T. J., Williams, T. J. 2006; 128 (46): 14814-14815

    Abstract

    The Rh(I)-catalyzed [3 + 2] cycloaddition of cyclopropenones and alkynes is found to provide a highly efficient and regiocontrolled route to cyclopentadienones (CPDs), building blocks of widespread use in the synthesis of natural and non-natural products, therapeutic leads, polymers, dendrimers, devices, and antigen presenting scaffolds. The versatility of the method is explored with 23 examples representing a wide range of alkyne variations (arylalkyl-, dialkyl-, heteroarylalkyl-) and diaryl- as well as arylalkylcyclopropenones. The reactions often proceed in high yield using minimal catalyst loadings and in all cases examined proceed with high or complete regioselectivity. The reaction is readily scalable to produce gram quantities of cycloadduct and provides a unique and versatile route to CPDs that would be otherwise difficult to obtain.

    View details for DOI 10.1021/ja065868p

    View details for Web of Science ID 000242021700040

    View details for PubMedID 17105285

  • Total synthesis and initial biological evaluation of new B-ring-modified bryostatin analogs ORGANIC LETTERS Wender, P. A., Horan, J. C., Verma, V. A. 2006; 8 (23): 5299-5302

    Abstract

    [Structure: see text] The total synthesis and preliminary biological evaluation of the first bryostatin analogs (bryologs) to incorporate B-ring substitution are reported. Asymmetric syntheses of two new polyketide "spacer" domains are described, one exploiting the pseudosymmetry of the C1-C13 region. These fragments are convergently joined to the "recognition" domain through a remarkably versatile macrotransacetalization process. The resulting new analogs exhibit potent nanomolar or picomolar affinity to protein kinase C (PKC), comparable to or better than that found for bryostatin.

    View details for DOI 10.1021/ol0620904

    View details for Web of Science ID 000241729500031

    View details for PubMedID 17078702

  • Studies on oxidopyrylium [5+2] cycloadditions: Toward a general synthetic route to the C12-hydroxy daphnetoxins ORGANIC LETTERS Wender, P. A., Bi, F. C., Buschmann, N., Gosselin, F., Kan, C., Kee, J., Ohmura, H. 2006; 8 (23): 5373-5376

    Abstract

    [Structure: see text] 12-hydroxydaphnetoxins, members of the structurally fascinating daphnane diterpene family, exhibit a wide range of significant biological activities. A general route to the BC-ring system of 12-hydroxy daphnetoxins is reported based on D-ribose. Depending on the choice of protecting groups and solvent, the oxidopyrylium-alkene [5+2] cycloaddition originating from A provides cycloadduct diastereomer B or C with good to excellent selectivity.

    View details for DOI 10.1021/ol062234e

    View details for Web of Science ID 000241729500050

    View details for PubMedID 17078721

  • Molecular transporters: Synthesis of oligoguanidinium transporters and their application to drug delivery and real-time imaging CHEMBIOCHEM Goun, E. A., Pillow, T. H., Jones, L. R., Rothbard, J. B., Wender, P. A. 2006; 7 (10): 1497-1515

    View details for DOI 10.1002/cbic.200600171

    View details for Web of Science ID 000241392400004

    View details for PubMedID 16972294

  • Synthesis and PKC binding of a new class of A-ring diversifiable bryostatin analogues utilizing a double asymmetric hydrogenation and cross-coupling strategy ORGANIC LETTERS Wender, P. A., Horan, J. C. 2006; 8 (20): 4581-4584

    Abstract

    The design, asymmetric synthesis, and biological evaluation of a new class of bryostatin analogues based on a pseudosymmetric spacer domain are described. An aryl bromide diversification site is incorporated allowing access to systematically varied analogues. The new analogues all exhibit potent, nanomolar affinity to PKC.

    View details for DOI 10.1021/ol0618149

    View details for Web of Science ID 000240654700050

    View details for PubMedID 16986955

  • Pharmacophore mapping in the laulimalide series: Total synthesis of a vinylogue for a late-stage metathesis diversification strategy ORGANIC LETTERS Wender, P. A., Hilinski, M. K., Skaanderup, P. R., Soldermann, N. G., Mooberry, S. L. 2006; 8 (18): 4105-4108

    Abstract

    An efficient synthesis of the macrocyclic core of laulimalide with a pendant vinyl group at C20 is described, allowing for late-stage introduction of various side chains through a selective and efficient cross metathesis diversification step. Representative analogues reported herein are the first to contain modifications to only the side chain dihydropyran of laulimalide and des-epoxy laulimalide. This step-economical strategy enables the rapid synthesis of new analogues using alkenes as an inexpensive, abundantly available diversification feedstock.

    View details for DOI 10.1021/ol061619u

    View details for Web of Science ID 000239990900055

    View details for PubMedID 16928085

  • New reactions and step economy: the total synthesis of (+/-)-salsolene oxide based on the type II transition metal-catalyzed intramolecular [4+4] cycloaddition TETRAHEDRON Wender, P. A., Croatt, M. P., Witulski, B. 2006; 62 (32): 7505-7511
  • Laulimalide and synthetic laulimalide analogues are synergistic with paclitaxel and 2-methoxyestradiol MOLECULAR PHARMACEUTICS Clark, E. A., Hills, P. M., Davidson, B. S., Wender, P. A., Mooberry, S. L. 2006; 3 (4): 457-467

    Abstract

    Some of the most significant therapeutic leads and agents used for the treatment of cancer target microtubule dynamics. Paclitaxel is an exceptional example that is currently used for treating a wide range of tumors. New, non-taxane microtubule stabilizers, including several epothilones, are advancing through clinical trials. Laulimalide is a potent microtubule stabilizer that binds to tubulin at a site that does not overlap the taxane-binding site. It is active against paclitaxel-resistant cancer cells. Notwithstanding its therapeutic potential, laulimalide is relatively unstable, rearranging to a more stable but less active isomer. The goal of this study was to evaluate the ability of laulimalide and two designed laulimalide analogues, C16-C17-des-epoxy laulimalide (LA1) and C20-methoxy laulimalide (LA2), to inhibit cell proliferation in combination with other tubulin-binding and non-tubulin-binding antiproliferative antimitotic agents. The synthetic laulimalide analogues retain the mechanism of action of the natural compound but do not share its instability. We studied the ability of the laulimalides to act synergistically with paclitaxel, 2-methoxyestradiol, and monastrol, an Eg5 kinesin inhibitor. The results show that all three of the laulimalides acted synergistically with paclitaxel and 2-methoxyestradiol to inhibit proliferation with the analogues exhibiting significantly larger synergistic effects. The combination of laulimalide and monastrol was not synergistic and provided only additive effects. The laulimalide analogues LA1 and LA2 had a greater degree of synergy with both paclitaxel and 2-methoxyestradiol than was observed with laulimalide. Our results show that the laulimalides together with other tubulin-binding antimitotic agents provide synergistic antiproliferative actions. The data are consistent with the previously reported ability of laulimalide and paclitaxel to act synergistically to polymerize tubulin in vitro. These important findings suggest that specific combinations of microtubule-targeting agents should be considered for clinical utilities as they have excellent potential to improve clinical response.

    View details for DOI 10.1021/mp060016h

    View details for Web of Science ID 000203539600011

    View details for PubMedID 16889440

  • Releasable luciferin-transporter conjugates: Tools for the real-time analysis of cellular uptake and release JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Jones, L. R., Goun, E. A., Shinde, R., Rothbard, J. B., Contag, C. H., Wender, P. A. 2006; 128 (20): 6526-6527

    Abstract

    The design, synthesis, and evaluation of conjugates of arginine-rich transporters and luciferin are described that release luciferin only after entry into cells that are stably transfected with luciferase. Each molecule of free luciferin that is released after entry generates a photon that can be measured allowing for real-time quantification of uptake and release in cells. The process provides a method to assay uptake and release of free luciferin as a function of variations in the releasable linker and in the transporter.

    View details for DOI 10.1021/ja0586283

    View details for Web of Science ID 000237590500002

    View details for PubMedID 16704230

  • Asymmetric catalysis of the [5+2] cycloaddition reaction of vinylcyclopropanes and pi-systems JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Wender, P. A., Haustedt, L. O., Lim, J., Love, J. A., Williams, T. J., Yoon, J. 2006; 128 (19): 6302-6303

    Abstract

    As part of our studies of metal-catalyzed [m + n (+...o)] cycloadditions, we have previously reported the rhodium-catalyzed [5 + 2] cycloaddition of vinylcyclopropanes (VCPs) and pi-systems. These studies have led to Rh(I) complexes that catalyze these reactions in minutes at room temperature or in water without organic solvents. We describe a comparative evaluation of several chiral catalysts for the [5 + 2] reaction, evaluation of a preferred catalyst, [((R)-BINAP)Rh]+SbF6-, with substrates differing in substitution and tether types-producing enantiomeric excesses >/=95% for several systems. A predictive model for the selectivity is also presented.

    View details for DOI 10.1021/ja058590u

    View details for Web of Science ID 000237590400017

    View details for PubMedID 16683779

  • Intracellular cargo delivery by an octaarginine transporter adapted to target prostate cancer cells through cell surface protease activation BIOCONJUGATE CHEMISTRY Goun, E. A., Shinde, R., Dehnert, K. W., Adams-Bond, A., Wender, P. A., Contag, C. H., Franc, B. L. 2006; 17 (3): 787-796

    Abstract

    Delivery of therapeutics and imaging agents to target tissues requires localization and activation strategies with molecular specificity. Cell-associated proteases can be used for these purposes in a number of pathologic conditions, and their enzymatic activities can be exploited for activation strategies. Here, molecules based on the d-arginine octamer (r8) protein-transduction domain (PTD, also referred to as molecular transporters) have been adapted for selective uptake into cells only after proteolytic cleavage of a PTD-attenuating sequence by the prostate-specific antigen (PSA), an extracellular protease associated with the surface and microenvironment of certain prostate cancer cells. Convergent syntheses of these activatable PTDs (APTDs) are described, and the most effective r8 PTD-attenuating sequence is identified. The conjugates are shown to be stable in serum, cleaved by PSA, and taken up into Jurkat (human T cells) and PC3M prostate cancer cell lines only after cleavage by PSA. These APTD peptide-based molecules may facilitate targeted delivery of therapeutics or imaging agents to PSA-expressing prostate cancers.

    View details for DOI 10.1021/bc0503216

    View details for Web of Science ID 000237576000029

    View details for PubMedID 16704219

  • Design, synthesis, and biological evaluation of a potent, PKC selective, B-ring analog of bryostatin ORGANIC LETTERS Wender, P. A., Verma, V. A. 2006; 8 (9): 1893-1896

    Abstract

    [structure: see text] The first member of a new class of five-membered B-ring analogs of bryostatin has been synthesized and tested for its ability to bind and translocate protein kinase C (PKC). This synthesis extends the utility of our previously introduced macrotransacetalization strategy to the formation of five-membered dioxolane B-ring analogs. This analog exhibits potent, single-digit nanomolar affinity to PKC and selectively translocates novel PKC isozymes.

    View details for DOI 10.1021/ol060457z

    View details for Web of Science ID 000237174500037

    View details for PubMedID 16623578

  • Rhodium(I)-catalyzed [4+2+2] cycloadditions of 1,3-dienes, alkenes, and alkynes for the synthesis of cyclooctadienes JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Wender, P. A., Christy, J. P. 2006; 128 (16): 5354-5355

    Abstract

    The first [4+2+2] cycloadditions involving terminal alkynes and diene-enes, including a fully intramolecular example, are reported resulting in the formation of cyclooctadienes using [RhCl(CO)2]2 (5 mol %) treated with AgSbF6 (10 mol %) as a precatalyst. The reaction is general for a variety of terminal alkynes, as well as variously substituted diene-enes (yields up to 88%).

    View details for DOI 10.1021/ja060878b

    View details for Web of Science ID 000237125100027

    View details for PubMedID 16620102

  • Total synthesis and biological evaluation of 11-desmethyllaulimalide, a highly potent simplified laulimalide analogue ORGANIC LETTERS Wender, P. A., Hilinski, M. K., Soldermann, N., Mooberry, S. L. 2006; 8 (7): 1507-1510

    Abstract

    [reaction: see text] A step-economical synthesis of 11-desmethyllaulimalide (2) is reported. This simplified analogue is available through an improved second-generation synthetic approach to the laulimalides, in a shorter step count and from much less expensive starting material than the parent compound. This new lead retains the anticancer function of laulimalide.

    View details for DOI 10.1021/o1060233g

    View details for Web of Science ID 000236397000064

    View details for PubMedID 16562928

  • Correlation of F0F1-ATPase inhibition and antiproliferative activity of apoptolidin analogues ORGANIC LETTERS Wender, P. A., Jankowski, O. D., Longcore, K., Tabet, E. A., Seto, H., Tomikawa, T. 2006; 8 (4): 589-592

    Abstract

    [structure: see text] Apoptolidin (1) exhibits potent and highly selective apoptosis inducing activity against sensitive cancer cell lines and is hypothesized to act by inhibition of mitochondrial F(0)F(1)-ATP synthase. A series of apoptolidin derivatives, including a new intermolecular Diels-Alder adduct, were analyzed for antiproliferative activity in E1A-transformed rat fibroblasts. Potent F(0)F(1)-ATPase inhibition was not a sufficient determinant of antiproliferative activity for several analogues, suggesting the existence of a secondary biological target or more complex mode of action for apoptolidin.

    View details for DOI 10.1021/ol052800q

    View details for Web of Science ID 000235534800011

    View details for PubMedID 16468718

  • Rh-I-catalyzed C-C bond activation: Seven-membered ring synthesis by a [6+1] carbonylative ring-expansion reaction of allenylcyclobutanes ANGEWANDTE CHEMIE-INTERNATIONAL EDITION Wender, P. A., Deschamps, N. M., Sun, R. 2006; 45 (24): 3957-3960

    View details for DOI 10.1002/anie.200600806

    View details for Web of Science ID 000238501500013

    View details for PubMedID 16683295

  • Molecular understanding of cellular uptake by arginine-rich cell penetrating peptides POLYMERIC DRUG DELIVERY I: PARTICULATE DRUG CARRIERS Rothbard, J. B., Jessop, T. C., Wender, P. A. 2006; 923: 166-181
  • Metal-catalyzed [2+2+1] cycloadditions of 1,3-dienes, allenes, and CO ANGEWANDTE CHEMIE-INTERNATIONAL EDITION Wender, P. A., Croatt, M. P., Deschamps, N. M. 2006; 45 (15): 2459-2462

    View details for DOI 10.1002/anie.200600300

    View details for Web of Science ID 000236768600029

    View details for PubMedID 16526073

  • Actin is the primary cellular receptor of bistramide A NATURE CHEMICAL BIOLOGY Statsuk, A. V., Bai, R. L., Baryza, J. L., Verma, V. A., Hamel, E., Wender, P. A., Kozmin, S. A. 2005; 1 (7): 383-388

    Abstract

    Bistramide A (1) is a marine natural product with broad, potent antiproliferative effects. Bistramide A has been reported to selectively activate protein kinase C (PKC) delta, leading to the view that PKCdelta is the principal mediator of antiproliferative activity of this natural product. Contrary to this observation, we established that bistramide A binds PKCdelta with low affinity, does not activate this kinase in vitro and does not translocate GFP-PKCdelta. Furthermore, we identified actin as the cellular receptor of bistramide A. We report that bistramide A disrupts the actin cytoskeleton, inhibits actin polymerization, depolymerizes filamentous F-actin in vitro and binds directly to monomeric G-actin in a 1:1 ratio with a Kd of 7 nM. We also constructed a fully synthetic9 bistramide A-based affinity matrix and isolated actin as a specific bistramide A-binding protein. This activity provides a molecular explanation for the potent antiproliferative effects of bistramide A, identifying it as a new biochemical tool for studies of the actin cytoskeleton and as a potential lead for development of a new class of antitumor agents.

    View details for DOI 10.1038/nchembio748

    View details for Web of Science ID 000233447700010

    View details for PubMedID 16372404

  • Dendrimeric molecular transporters: Synthesis and evaluation of tunable polyguanidino dendrimers that facilitate cellular uptake ORGANIC LETTERS Wender, P. A., Kreider, E., Pelkey, E. T., Rothbard, J., VanDeusen, C. L. 2005; 7 (22): 4815-4818

    Abstract

    [reaction: see text] Nine fluorescently labeled structurally varied polyguanidino dendrimers based on diamino acid monomeric units were individually synthesized in an efficient, scalable sequence using a trifluoroacetamide protecting group-perguanidinylation strategy. While the dendrimers varied significantly in their ability to enter a human lymphocyte cell line, the best transporters out-performed an oligoarginine reference standard.

    View details for DOI 10.1021/ol051496y

    View details for Web of Science ID 000232817700008

    View details for PubMedID 16235896

  • Apoptolidins B and C: Isolation, structure determination, and biological activity ORGANIC LETTERS Wender, P. A., Sukopp, M., Longcore, K. 2005; 7 (14): 3025-3028

    Abstract

    [reaction: see text] Apoptolidin (1) is a promising new therapeutic lead that exhibits remarkable selectivity against cancer cells relative to normal cells. We report the isolation, characterization, solution structure, stability, and biological activity of two new members of this family: apoptolidins B (2) and C (3). These new agents are found to have antiproliferative activity on par with or better than apoptolidin itself in an assay with H292 lung cancer cells.

    View details for DOI 10.1021/ol051074o

    View details for Web of Science ID 000230213100056

    View details for PubMedID 15987196

  • Rh(I)-catalyzed cleavage of unactivated C-O bonds - Carbonylative rearrangement reactions of allenyl ethers to 2-carboalkoxy-1,3-dienes CANADIAN JOURNAL OF CHEMISTRY Wender, P. A., Deschamps, N. M., Sun, R. 2005; 83 (6-7): 838-842

    View details for DOI 10.1139/V05-085

    View details for Web of Science ID 000231832500041

  • Role of the A-ring of bryostatin analogues in PKC binding: Synthesis and initial biological evaluation of new A-ring-modified bryologs ORGANIC LETTERS Wender, P. A., Clarke, M. O., Horan, J. C. 2005; 7 (10): 1995-1998

    Abstract

    The syntheses of three newly designed bryostatin analogues are reported. These simplified analogues, which lack the A-ring present in the natural product but possess differing groups at C9, were obtained using a divergent approach from a common intermediate. All three analogues exhibit potent, single-digit nanomolar affinity to protein kinase C.

    View details for DOI 10.1021/ol0504650

    View details for Web of Science ID 000228984500028

    View details for PubMedID 15876038

  • Transition metal-catalyzed intermolecular [5+2] and [5+2+1] cycloadditions of allenes and vinylcyclopropanes JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Wegner, H. A., de Meijere, A., Wender, P. A. 2005; 127 (18): 6530-6531

    Abstract

    Initial examples of the intermolecular Rh(I)-catalyzed [5+2] cycloaddition reaction of bifunctional allenes and vinylcyclopropanes are described. The reactions proceed with facility and in yields of up to 99% with a variety of alkyne-, ester-, styrene-, or cyano-substituents on the allene to afford the corresponding cycloadducts. In the presence of CO, the reaction proceeds to an eight-membered ring cycloadduct and its transannularly closed product, providing the first example of a three-component [5+2+1] cycloaddition with allenes.

    View details for DOI 10.1021/ja043671w

    View details for Web of Science ID 000229055800015

    View details for PubMedID 15869263

  • Identification of a tunable site in bryostatin analogs: C20 bryologs through late stage diversification ORGANIC LETTERS Wender, P. A., Baryza, J. L. 2005; 7 (6): 1177-1180

    Abstract

    [structure: see text] The C20 region of our bryostatin analogs was identified as a nonpharmacophoric site that could be varied to tune analogs for function and physical properties without significantly affecting their binding affinity for PKC. The use of this site in a late-stage diversification strategy has enabled the facile synthesis of a variety of new C20 analogs, all of which retain nanomolar affinity for PKC, in agreement with our pharmacophore hypothesis.

    View details for DOI 10.1021/ol0501931

    View details for Web of Science ID 000227621000056

    View details for PubMedID 15760168

  • Multicomponent cycloadditions: The four-component [5+1+2+1] cycloaddition of vinylcyclopropanes, alkynes, and CO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Wender, P. A., Gamber, G. G., Hubbard, R. D., Pham, S. M., Zhang, L. 2005; 127 (9): 2836-2837

    Abstract

    Prompted by the view that intermediates of transition metal-catalyzed reactions could be intercepted by one or more additional components, studies in our laboratory have led to the design and development of new three-component [5+2+1], [4+2+1], and [2+2+1] cycloadditions. These continuing studies have now led to the identification of a fundamentally new four-component [5+1+2+1] cycloaddition reaction of vinylcyclopropanes, alkynes and CO, yielding hydroxyindanone products in generally good yields. Terminal alkynes bearing aryl or alkyl groups are tolerated well. Substitution at any position of the VCP leads predictably to substituted hydroxyindanone products. Using a bis-alkynyl substrate, the reaction can be carried out bi-directionally, forming 10 C-C bonds and four new rings from seven components in a single, operationally simple process.

    View details for DOI 10.1021/ja042728b

    View details for Web of Science ID 000227479600021

    View details for PubMedID 15740103

  • Adaptive translocation: the role of hydrogen bonding and membrane potential in the uptake of guanidinium-rich transporters into cells ADVANCED DRUG DELIVERY REVIEWS Rothbard, J. B., Jessop, T. C., Wender, P. A. 2005; 57 (4): 495-504

    Abstract

    A mechanistic hypothesis is presented for how water-soluble guanidinium-rich transporters attached to small cargoes (MW ca. <3000) can migrate across the non-polar lipid membrane of a cell and enter the cytosol. Positively charged and water-soluble, arginine oligomers can associate with negatively charged, bidentate hydrogen bond acceptor groups of endogenous membrane constituents, leading to the formation of membrane-soluble ion pair complexes. The resultant less polar, ion pair complexes partition into the lipid bilayer and migrate in a direction, and with a rate, influenced by the membrane potential. The complex dissociates on the inner leaf of the membrane and the transporter conjugate enters the cytosol. This mechanism could also be involved in the translocation of guanidinium-rich molecules that are endocytosed due to their size or the conditions of the assay, across the endosomal membrane.

    View details for DOI 10.1016/j.addr.2004.10.003

    View details for Web of Science ID 000227570500003

    View details for PubMedID 15722160

  • Late-stage intermolecular CH activation for lead diversification: A highly chemoselective oxyfunctionalization of the C-9 position of potent bryostatin analogues ORGANIC LETTERS Wender, P. A., Hilinski, M. K., Mayweg, A. V. 2005; 7 (1): 79-82

    Abstract

    Treatment of highly potent and densely functionalized bryostatin analogue 1 with dimethyldioxirane afforded the C-9 hydroxylated hemiketal 2 via oxyfunctionalization of the C9-CH bond, one of 12 CH bonds geminal to an oxygen substituent in 1. When bryostatin analogue 3 was subjected to identical conditions, oxidation of a C-26 secondary hydroxyl group was found to compete with C-9 hydroxylation. Complete selectivity for C-9 hydroxylation was restored upon acylation of the C-26 secondary alcohol.

    View details for DOI 10.1021/o1047859w

    View details for Web of Science ID 000226072100020

    View details for PubMedID 15624982

  • Effect of serum and antioxidants on the immunogenicity of protein kinase C-activated chronic lymphocytic leukemia cells JOURNAL OF IMMUNOTHERAPY Hammond, C., Shi, Y. H., Mena, J., Tomic, J., Cervi, D., He, L. W., Millar, A. E., DeBenedette, M., Schuh, A. C., Baryza, J. L., Wender, P. A., Radvanyi, L., Spaner, D. E. 2005; 28 (1): 28-39

    Abstract

    Since the intrinsically poor immunogenicity of chronic lymphocytic leukemia (CLL) cells might be a key factor in allowing them to avoid immune control mechanisms, the development of methods to enhance CLL cell immunogenicity might lead to improved disease control. The ability of CLL cells to stimulate T cells was increased significantly by the protein kinase C (PKC) agonist phorbol myristic acetate (PMA). However, under serum-free conditions, PMA-activated CLL cells died within 48 hours. Antioxidants, such as 2-mercaptoethanol (2-ME), or fetal calf serum could prevent the death of these cells but caused them to enter distinct states of differentiation. In the presence of 2-ME, PMA-activated CLL cells extended dendritic-like protrusions and exhibited increased T-cell stimulatory capacity. In the presence of serum, PMA-activated CLL cells developed fewer dendrites, made less IL-10 and more IL-12 p40 mRNA transcripts, and showed an increased capacity to induce IFN-gamma production by T cells. The effects of serum on the promotion of type 1 immune responses by phorbol ester-activated CLL cells were dominant and correlated with activation of the NF-kappaB signaling pathway. Other PKC agonists, such as Bryostatin-1 and a synthetic Bryostatin analog (Picolog), had similar effects on CLL cells. The observation that CLL cells can acquire features of dendritic cells that promote type 1 immunity may find clinical application in immunotherapeutic strategies for this disease.

    View details for Web of Science ID 000226087300004

    View details for PubMedID 15614042

  • Synthetic bryostatin analogues activate the RasGRP1 signaling pathway JOURNAL OF MEDICINAL CHEMISTRY Stone, J. C., Stang, S. L., Zheng, Y., Dower, N. A., Brenner, S. E., Baryza, J. L., Wender, P. A. 2004; 47 (26): 6638-6644

    Abstract

    The functional properties of four diacylglycerol (DAG) analogues were compared using cell-signaling assays based on the protein RasGRP1, a DAG-regulated Ras activator. Compounds 1 and 2, synthetic analogues of bryostatin 1, were compared to authentic bryostatin 1 and phorbol 12-myristate-13-acetate (PMA). The two "bryologues" were able to activate RasGRP1 signaling rapidly in cultured cells and isolated mouse thymocytes. They elicited expression of the T cell activation marker CD69 in human T cells. DAG analogues promptly recruited RasGRP1 to cell membranes, but they did not induce RasGRP1 proteolysis. Bryostatin 1 and compounds 1 and 2 appeared to be less potent than PMA at inducing aggregation of mouse thymocytes, a PKC-dependent, RasGRP1-independent response. In addition to sharing potential anticancer properties with bryostatin 1, compounds 1 and 2 might be clinically useful as modulators of the immune system.

    View details for DOI 10.1021/jm0495069

    View details for Web of Science ID 000225748500026

    View details for PubMedID 15588099

  • Simplified analogs of bryostatin with anticancer activity display greater potency for translocation of PKC delta-GFP CHEMISTRY & BIOLOGY Baryza, J. L., Brenner, S. E., Craske, M. L., Meyer, T., Wender, P. A. 2004; 11 (9): 1261-1267

    Abstract

    Structurally simplified analogs of bryostatin 1, a marine natural product in clinical trials for the treatment of cancer, have been shown to be up to 50 times more potent than bryostatin 1 at inducing the translocation of PKCdelta-GFP from the cytosol of rat basophilic leukemia (RBL) cells. The end distribution of the protein is similar for all three compounds, despite a significant difference in translocation kinetics. The potency of the compounds for inducing the translocation response appears to be only qualitatively related to their binding affinity for PKC, highlighting the importance of using binding affinity in conjunction with real-time measurements of protein localization for the pharmacological profiling of biologically active agents.

    View details for DOI 10.1016/j.chembiol.2004.06.014

    View details for Web of Science ID 000224228900009

    View details for PubMedID 15380186

  • Role of membrane potential and hydrogen bonding in the mechanism of translocation of guanidinium-rich peptides into cells JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Rothbard, J. B., Jessop, T. C., Lewis, R. S., Murray, B. A., Wender, P. A. 2004; 126 (31): 9506-9507

    Abstract

    The results described herein support a mechanistic hypothesis for how guanidine-rich transporters attached to small cargos (MW ca. <3000) can migrate across the lipid membrane of a cell and directly enter the cytosol. Arginine oligomers are found to partition almost completely into the aqueous layer of a water-octanol bilayer. However, when the same partitioning experiment is conducted in the presence of sodium laurate, a representative negatively charged membrane constituent, the arginine oligomer partitions almost completely (>95%) into the octanol layer. In contrast, ornithine oligomers partition almost exclusively into the water layer with and without added sodium laurate. The different partitioning between guanidinium-rich and ammonium-rich oligomers in the presence of sodium laurate is consistent with the ability of the former to form a bidentate hydrogen bonded ion pair. Mono- and dimethylated arginine oligomers, which like ornithine can only efficiently form monodentate hydrogen bonds, were prepared and found to exhibit poor cellular uptake. Ion pair formation converts a once water-soluble agent to a lipid-soluble agent, thereby reducing the energetic penalty for passage of guanidine-rich transporters through the lipid bilayer. Uptake of guanidine-rich transporters is known to be an energy-dependent process, and this requirement for cellular ATP is now rationalized by the inhibition of guanidine-rich transporter uptake in the presence of agents that reduce the membrane potential. Specifically, incubation of cells in buffers with high potassium ion concentrations or pretreatment of cells with gramicidin A reduces the cellular uptake of Fl-aca-arg8-CONH2 by >90%. Furthermore, the reciprocal experiment of hyperpolarizing the cell with valinomycin increased uptake by >1.5 times. In summary, we propose that the water-soluble, positively charged guanidinium headgroups of the transporter form bidentate hydrogen bonds with H-bond acceptor functionality on the cell surface. The resultant ion pair complexes partition into the lipid bilayer and migrate across at a rate related to the membrane potential. The complex dissociates on the inner leaf of the membrane, and the transporter enters the cytosol. This hypothesis does not preclude uptake by other mechanisms, including endocytosis, which is likely to dominate with large cargos.

    View details for DOI 10.1021/ja0482536

    View details for Web of Science ID 000223110100020

    View details for PubMedID 15291531

  • On the mechanism of [Rh(CO)(2)Cl](2)-catalyzed intermolecular (5+2) reactions between vinylcyclopropanes and alkynes JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Yu, Z. X., Wender, P. A., Houk, K. N. 2004; 126 (30): 9154-9155

    Abstract

    DFT calculations have been applied to investigate the reaction mechanism of rhodium dimer, [Rh(CO)2Cl]2, catalyzed intermolecular (5 + 2) reactions between vinylcyclopropanes and alkynes. The catalytic species is Rh(CO)Cl and the catalytic cycle is through the sequential reactions of cyclopropyl cleavage of vinylcyclopropane, alkyne insertion (rate-determining step), and a migratory reductive elimination.

    View details for DOI 10.1021/ja048739m

    View details for Web of Science ID 000222950900003

    View details for PubMedID 15281784

  • Nanotube molecular transporters: Internalization of carbon nanotube-protein conjugates into mammalian cells JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Kam, N. W., Jessop, T. C., Wender, P. A., Dai, H. J. 2004; 126 (22): 6850-6851

    Abstract

    The interactions between various functionalized carbon nanotubes and several types of human cancer cells are explored. We have prepared modified nanotubes and have shown that these can be derivatized in a way that enables attachment of small molecules and of proteins, the latter through a novel noncovalent association. The functionalized carbon nanotubes enter nonadherent human cancer cells as well as adherent cell lines (CHO and 3T3) and by themselves are not toxic. While the fluoresceinated protein streptavidin (MW approximately 60 kD) by itself does not enter cells, it readily enters cells when complexed to a nanotube-biotin transporter and exhibits dose-dependent cytotoxicity. The uptake pathway is consistent with adsorption-mediated endocytosis. The use of carbon nanotubes as molecular transporters could be exploited for various cargos. The biocompatibility and unique physical, electrical, optical, and mechanical properties of nanotubes provide the basis for new classes of materials for drug, protein, and gene delivery applications.

    View details for DOI 10.1021/ja0486059

    View details for Web of Science ID 000221828200007

    View details for PubMedID 15174838

  • Microtubule-stabilizing agents based on designed laulimalide analogues PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Mooberry, S. L., Randall-Hlubek, D. A., Leal, R. M., Hegde, S. G., Hubbard, R. D., Zhang, L., Wender, P. A. 2004; 101 (23): 8803-8808

    Abstract

    Laulimalide is a potent, structurally unique microtubule-stabilizing agent originally isolated from the marine sponge Cacospongia mycofijiensis. Laulimalide exhibits an activity profile different from other microtubule-binding agents, notably including effectiveness against paclitaxel-resistant cells, but it is intrinsically unstable. Five analogues of laulimalide were designed to exhibit enhanced chemical stability yet retain its exceptional biological activities. Evaluations of these analogues showed that all are effective inhibitors of cancer-cell proliferation yet differ substantially in potency with an IC(50) range of 0.12-16.5 microM. Although all of the analogues initiated cellular changes similar to laulimalide, including increased density of interphase microtubules, aberrant mitotic spindles, and ultimately apoptosis, differences among the analogues were apparent. The two most potent analogues, C(16)-C(17)-des-epoxy laulimalide and C(20)-methoxy laulimalide, appear to have a mechanism of action identical to laulimalide. The C(16)-C(17)-des-epoxy, C(20)-methoxy laulimalide derivative, which incorporates both chemical changes of the most potent analogues, was significantly less potent and initiated the formation of unique interphase microtubules unlike the parent compound and other analogues. Two C(2)-C(3)-alkynoate derivatives had lower potency, and they initiated abnormal microtubule structures but did not cause micronucleation or extensive G(2)/M accumulation. Significantly, paclitaxel- and epothilone-resistant cell lines were less resistant to the laulimalide analogues. In summary, analogues of laulimalide designed to minimize or eliminate its intrinsic instability have been synthesized, and some have been found to retain the unique biological activities of laulimalide.

    View details for Web of Science ID 000222037000056

    View details for PubMedID 15161976

  • Rhodium(I)-Catalyzed [2+2+1] cycloadditions of 1,3-dienes, alkenes, and CO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Wender, P. A., Croatt, M. P., Deschamps, N. M. 2004; 126 (19): 5948-5949

    Abstract

    Initial examples of a Rh(I)-catalyzed [2+2+1] reaction of diene-enes and CO are described. This method allows for the facile, efficient, and diastereoselective construction of a variety of alkenyl cyclopentanones in good to excellent yields. Control studies show that the diene moiety is required for this process as bis-enes do not give the [2+2+1] products under the same conditions.

    View details for Web of Science ID 000221416700010

    View details for PubMedID 15137743

  • Function oriented synthesis: the design, synthesis, PKC binding and translocation activity of a new bryostatin analog. Current drug discovery technologies Wender, P. A., Baryza, J. L., Brenner, S. E., Clarke, M. O., Craske, M. L., Horan, J. C., Meyer, T. 2004; 1 (1): 1-11

    Abstract

    Bryostatin 1 represents a novel and potent therapeutic lead with a unique activity profile. Its natural and synthetic availability is severely limited. Function oriented synthesis provides a means to address this supply problem through the design of synthetically more accessible simplified structures that at the same time incorporate improved functional activity. Pharmacophore searching and a new computer aided visualization of a possible binding mode are combined with an understanding of function and knowledge of synthesis to design and prepare a new and simplified compound with bryostatin-like function in biological systems. This new compound is a potent ligand for protein kinase C in vitro (K(i) = 8.0 nM). More significantly, the described molecule retains the functional ability to translocate a PKCdelta-GFP fusion protein in RBL cells. The extent of protein translocation and the sub-cellular localization induced by this new compound is similar to that seen in response to bryostatin 1, indicating that the new molecule retains the functional activity of the natural product but is simpler and can be synthesized in a practical fashion.

    View details for PubMedID 16472215

  • Intermolecular dienyl Pauson-Khand reaction ANGEWANDTE CHEMIE-INTERNATIONAL EDITION Wender, P. A., Deschamps, N. M., Williams, T. T. 2004; 43 (23): 3076-3079

    View details for DOI 10.1002/anie.200454117

    View details for Web of Science ID 000222067400021

    View details for PubMedID 15188486

  • A new synthetic approach to the C ring of known as well as novel bryostatin analogues ORGANIC LETTERS Wender, P. A., Koehler, M. F., Sendzik, M. 2003; 5 (24): 4549-4552

    Abstract

    [reaction: see text] A new approach to the synthesis of the C ring subunit of known and potential bryostatin analogues is described. The convergent approach, illustrated above, requires fewer steps and offers greater flexibility in rapidly accessing diverse C ring analogues.

    View details for DOI 10.1021/ol0355332

    View details for Web of Science ID 000186728600005

    View details for PubMedID 14627380

  • Synthesis and biological evaluation of (-)-laulimalide analogues ORGANIC LETTERS Wender, P. A., Hegde, S. G., Hubbard, R. D., Zhang, L., Mooberry, S. L. 2003; 5 (19): 3507-3509

    Abstract

    [reaction: see text] The syntheses of five laulimalide analogues are described, incorporating modifications at the C(16)-C(17)-epoxide, the C(20)-alcohol, as well as the C(1)-C(3)-enoate of the parent natural product. The resultant analogues are active in drug-sensitive HeLa and MDA-MB-435 cell lines. Significantly, like laulimalide, these analogues are poor substrates for the drug transport protein P-glycoprotein (Pgp) and are thus effective against Taxol-resistant cell lines.

    View details for DOI 10.1021/ol035339f

    View details for Web of Science ID 000185329300036

    View details for PubMedID 12967311

  • Arginine-based molecular transporters: The synthesis and chemical evaluation of releasable taxol-transporter conjugates ORGANIC LETTERS Kirschberg, T. A., VanDeusen, C. L., Rothbard, J. B., Yang, M., Wender, P. A. 2003; 5 (19): 3459-3462

    Abstract

    [structure: see text] A flexible and efficient procedure has been developed for the conjugation of taxol to various arginine-based molecular transporters via the taxol C2' O-chloroacetyl derivative. The resultant taxol-transporter conjugates are highly water soluble and release free taxol with half-lives of minutes to hours depending on the pH and the linker structure.

    View details for DOI 10.1021/ol035234c

    View details for Web of Science ID 000185329300024

    View details for PubMedID 12967299

  • Gene transfer via reversible plasmid condensation with cysteine-flanked, internally spaced arginine-rich peptides HUMAN GENE THERAPY Siprashvili, Z., Scholl, F. A., Oliver, S. F., Adams, A., Contag, C. H., Wender, P. A., Khavari, P. A. 2003; 14 (13): 1225-1233

    Abstract

    Nonviral gene transfer offers biosafety, stability, and expense advantages over viruses; however, it has suffered from poor efficiency. Because arginine-rich peptides facilitate uptake of macromolecules such as proteins, liposomes, and iron nanoparticles, we explored their potential in enhancing plasmid DNA delivery. In their unmodified form, known protein transduction sequences, including hepta-arginine and Tat(47-57), failed to support effective gene delivery. However, by flanking a core of consecutive arginines with amino- and carboxy-terminal cysteines in vitro gene transfer was observed. Furthermore, interspersing arginines with glycine and histidine residues achieved reversible plasmid condensation and dramatically increased transfection levels in a variety of cell types. Unlike most available cationic homopolymers that function only in vitro, these new peptides also increased gene expression in both murine and human tissue in vivo. Thus, cysteine-flanked, internally spaced arginine-rich (CFIS-R) peptides represent a new approach to efficient nonviral plasmid delivery using rationally designed protein transduction domains.

    View details for Web of Science ID 000184794500002

    View details for PubMedID 12952594

  • Facile synthetic access to and biological evaluation of the macrocyclic core of apoptolidin ORGANIC LETTERS Wender, P. A., Jankowski, O. D., Tabet, E. A., Seto, H. 2003; 5 (13): 2299-2302

    Abstract

    Oxidative cleavage of the C-20/C-21 bond in apoptolidin (1) provides two fragments of similar complexity, facilitating a divide-and-diversify strategy for the determination of the structural basis for apoptolidin's biological activity, the remarkably selective induction of apoptosis in sensitive cell lines. The ability of compounds derived from this cleavage to inhibit mitochondrial F(0)F(1)-ATPase is reported. [structure: see text]

    View details for DOI 10.1021/ol0346335

    View details for Web of Science ID 000183692600027

    View details for PubMedID 12816433

  • Photoinduced cleavage of DNA by bromofluoroacetophenone-pyrrolecarboxamide conjugates BIOORGANIC & MEDICINAL CHEMISTRY LETTERS Wender, P. A., Jeon, R. 2003; 13 (10): 1763-1766

    Abstract

    Bromofluoroacetophenone derivatives which produce fluorine substituted phenyl radicals that cleave DNA upon excitation were investigated as a novel photonuclease. Pyrrolecarboxamide-conjugated bromofluoroacetophenones; 4'-bromo-2'-fluoroacetophenone and 2'-bromo-4'-fluoroacetophenone were synthesized and their DNA cleaving activities and sequence selectivities were determined. Bromofluoroacetophenone-pyrrolecarboxamide conjugates were found to be effective DNA cleaving agents upon irradiation in concentration dependent manner based on plasma relaxation assay. The DNA cleaving activities of 2'-bromo-4'-fluoroacetophenone derivatives were larger than those of 4'-bromo-2'-fluoroacetophenone derivatives.

    View details for DOI 10.1016/S0960-894X(03)00212-9

    View details for Web of Science ID 000182913600034

    View details for PubMedID 12729660

  • Guanidinium rich peptide transporters and drug delivery CURRENT PROTEIN & PEPTIDE SCIENCE Wright, L. R., Rothbard, J. B., Wender, P. A. 2003; 4 (2): 105-124

    Abstract

    The use of peptide or peptidomimetic transporters to enable or enhance the uptake of drugs or probe molecules into cells and tissues has received increasing research attention and clinical interest over the past 10 years. This review summarizes a class of transporters that have been studied and focuses on the variation and use of guanidinium based transporters to facilitate the uptake of various types of molecules into cells and tissues. Lead conjugates in this area are currently in clinical trials.

    View details for Web of Science ID 000181704200004

    View details for PubMedID 12678850

  • Toward a structure-activity relationship for apoptolidin: Selective functionalization of the hydroxyl group array ORGANIC LETTERS Wender, P. A., Jankowski, O. D., Tabet, E. A., Seto, H. 2003; 5 (4): 487-490

    Abstract

    [reaction: see text] To investigate the structural basis for the exceptional selectivity and activity of apoptolidin (1), a strategy has been devised that allows for selective functionalization of seven of its eight hydroxyl groups based on progressive silyl protection, derivatization, and deprotection. The syntheses of these derivatives and their ability to inhibit F(0)F(1)-ATPase are reported.

    View details for DOI 10.1021/ol027366w

    View details for Web of Science ID 000181077200027

    View details for PubMedID 12583750

  • A concise, selective synthesis of the polyketide spacer domain of a potent bryostatin analogue ORGANIC LETTERS Wender, P. A., Mayweg, A. V., VanDeusen, C. L. 2003; 5 (3): 277-279

    Abstract

    [reaction: see text] A concise, asymmetric synthesis of the polyketide spacer domain portion (C1-C13) of a highly potent bryostatin analogue was developed. The route utilizes asymmetric hydrogenation methodology to install the C3, C5, and C11 stereocenters, while a substrate directed syn reduction sets the C9 stereocenter. The spacer domain 1 is obtained in 10 steps with a 25% overall yield and is readily incorporated into the synthesis of 2.

    View details for DOI 10.1021/ol0272390

    View details for Web of Science ID 000180766400012

    View details for PubMedID 12556171

  • The dienyl Pauson-Khand reaction ANGEWANDTE CHEMIE-INTERNATIONAL EDITION Wender, P. A., Deschamps, N. M., Gamber, G. G. 2003; 42 (16): 1853-1857

    View details for Web of Science ID 000182751700018

    View details for PubMedID 12722081

  • Rhodium-catalyzed [5+2] cycloaddition reactions in water SYNLETT Wender, P. A., Love, J. A., Williams, T. J. 2003: 1295-1298
  • Transition metal-catalyzed hetero-[5+2] cycloadditions of cyclopropyl imines and alkynes: Dihydroazepines from simple, readily available starting materials JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Wender, P. A., Pedersen, T. M., Scanio, M. J. 2002; 124 (51): 15154-15155

    Abstract

    The first example of a transition metal-catalyzed hetero-[5 + 2] cycloaddition reaction is described. Use of cyclopropyl imines as five-atom components, an alkyne as a two-carbon component, and a Rh(I) catalyst enables a new route to dihydroazepines. This new hetero-[5 + 2] cycloaddition works well with aldimines, ketimines, and with substituted cyclopropanes and affords the desired dihydroazepines in excellent yields as single regioisomers. Use of serial imine formation/aza-[5 + 2] cycloaddition generates the desired dihydroazepines in one operation from three commercially available starting materials. The reaction has been scaled to give gram quantities of dihydroazepine.

    View details for DOI 10.1021/ja0285013

    View details for Web of Science ID 000180006600005

    View details for PubMedID 12487573

  • The practical synthesis of a novel and highly potent analogue of bryostatin JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Wender, P. A., Baryza, J. L., Bennett, C. E., Bi, C., Brenner, S. E., Clarke, M. O., Horan, J. C., Kan, C., Lacote, E., Lippa, B., Nell, P. G., Turner, T. M. 2002; 124 (46): 13648-13649

    Abstract

    Macrocycle 1 is a new highly potent analogue of bryostatin 1, a promising anti-cancer agent currently in human clinical trials. In vitro, 1 displays picomolar affinity for PKC and exhibits over 100-fold greater potency than bryostatin 1 when tested against various human cancer cell lines. Macrocycle 1 can be generated in clinically required amounts by chemical synthesis in only 19 steps (LLS) and represents a new clinical lead for the treatment of cancer.

    View details for DOI 10.1021/ja027509+

    View details for Web of Science ID 000179269800004

    View details for PubMedID 12431074

  • Oligocarbamate molecular transporters: Design, synthesis, and biological evaluation of a new class of transporters for drug delivery JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Wender, P. A., Rothbard, J. B., Jessop, T. C., Kreider, E. L., Wylie, B. L. 2002; 124 (45): 13382-13383

    Abstract

    Molecular transporters have the ability to deliver drugs and probe molecules into cells and tissues irrespective of their physical properties. We now report the design, synthesis, and biological evaluation of a new family of molecular transporters, guanidinylated oligocarbamates that enable exceptionally efficient uptake into cells and tissues. The synthesis features a solid-phase stepwise oligomerization to obtain the oligocarbamates and a single step perguanidinylation for the facile introduction of up to nine guanidinium groups. The oligocarbamate 9-mer is found to be among the most efficient transporters known, entering cells faster than even d-Arg9 and HIV-1 Tat49-57. Significantly, this new family of transporters also enables uptake into the formidable skin barrier of a probe molecule that by itself does not penetrate skin.

    View details for DOI 10.1021/ja0275109

    View details for Web of Science ID 000179122900022

    View details for PubMedID 12418880

  • Isoapoptolidin: Structure and activity of the ring-expanded isomer of apoptolidin ORGANIC LETTERS Wender, P. A., Gulledge, A. V., Jankowski, O. D., Seto, H. 2002; 4 (22): 3819-3822

    Abstract

    [formula: see text] Apoptolidin (1) is a novel oncolytic lead that induces apoptosis in transformed cell lines with exceptional selectivity. We report the isolation and characterization of a ring-expanded macrolide isomer of apoptolidin: isoapoptolidin (2). The solution conformation of isoapoptolidin is described. The rate of isomerization was measured under biologically relevant conditions and found to approach equilibrium within the time frame of most cell-based assays. Isoapoptolidin's ability to inhibit mitochondrial F0F1-ATPase is over 10-fold less than that of apoptolidin.

    View details for DOI 10.1021/o10266222

    View details for Web of Science ID 000178877500012

    View details for PubMedID 12599467

  • Arginine-rich molecular transporters for drug delivery: Role of backbone spacing in cellular uptake JOURNAL OF MEDICINAL CHEMISTRY Rothbard, J. B., Kreider, E., VanDeusen, C. L., Wright, L., Wylie, B. L., Wender, P. A. 2002; 45 (17): 3612-3618

    Abstract

    Short oligomers of arginine, either alone or when conjugated to therapeutic agents or large biopolymers, have been shown to cross readily a variety of biological barriers (e.g., lipid bilayers and epithelial tissue). Molecular modeling suggests that only a subset of the side chain guanidinium groups of these transporters might be required for transport involving contact with a common surface such as a plasma membrane or cell surface receptor. To evaluate this hypothesis, a series of decamers were prepared that incorporated seven arginines and three nonarginine residues. Several of these mixed decamers were comparable to the all arginine decamer in their ability to enter cells. More significantly, these decamers containing seven arginines performed almost without exception better than heptaarginine itself, suggesting that spacing between residues is also important for transport. The influence of spacing was more fully evaluated with a library of oligomers incorporating seven arginines separated by one or more nonconsecutive, non-alpha-amino acids. This study led to the identification of a new series of highly efficient molecular transporters.

    View details for DOI 10.1021/jm0105676

    View details for Web of Science ID 000177346400008

    View details for PubMedID 12166934

  • Peptide delivery to tissues via reversibly linked protein transduction sequences BIOTECHNIQUES Robbins, P. B., Oliver, S. F., Sheu, S. M., Goodnough, J. B., Wender, P., Khavari, P. A. 2002; 33 (1): 190-?

    Abstract

    The development of peptide-based therapeutics has suffered from challenges associated with delivery to intact tissue. In skin, an array of protein targets resides only tens of micrometers below the surface; however, because of difficulties in traversing the cutaneous barrier, the potentialfor peptide-based therapeutics remains unrealized. We have developed a general approach for topical peptide delivery into skin using releasable protein transduction sequences to enable peptide transport across tissue boundaries. Upon entry into the cell, the disulfide linkage between the peptide transduction sequences and peptide cargo is cleaved, permitting the dissociation of the highly charged peptide transduction sequences from the active peptide. A protype cargo peptide, the hemagglutinin (HA) epitope, was conjugated to a hepta-arginine protein transduction sequence via a releasable disulfide linkage. This construct penetrated the skin to deep dermis within 1 h after topical application. Consistent with the dissociation of the protein transduction and cargo sequences, absorbed protein transduction sequences and HA peptides displayed differential intracellular localization. Reversible protein transduction sequence linkage thus represents a noninvasive platform for tissue delivery of intact peptides with no requirement for viral vectors or parenteral injection and may be of broad utility in molecular therapy.

    View details for Web of Science ID 000176966000024

    View details for PubMedID 12139245

  • Total synthesis of (-)-laulimalide JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Wender, P. A., Hegde, S. G., Hubbard, R. D., Zhang, L. 2002; 124 (18): 4956-4957

    Abstract

    (-)-Laulimalide (1), a structurally novel macrolide isolated in trace amounts from marine sponges, promotes abnormal tubulin polymerization and apoptosis in vitro, with a similar mode of action to that of Taxol(R), but with potentially less susceptibility to multidrug resistance. Herein, a flexible and convergent asymmetric synthesis of (-)-laulimalide is described. This synthesis featured a highly diastereoselective Sakurai reaction of 2 with 3 and a regioselective macrolactonization of an unprotected vicinal diol. Laulimalide was synthesized in 25 steps (longest linear; 36 overall) in 3.5% overall yield, providing a uniquely short and efficient route to 1 and its analogues.

    View details for DOI 10.1021/ja0258428

    View details for Web of Science ID 000175369100012

    View details for PubMedID 11982349

  • Three-component cycloadditions: The first transition metal-catalyzed [5+2+1] cycloaddition reactions JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Wender, P. A., Gamber, G. G., Hubbard, R. D., Zhang, L. 2002; 124 (12): 2876-2877

    Abstract

    Prompted by our studies of transition metal-catalyzed [4+4], [4+2], [5+2], and [6+2] cycloadditions and by the view that these two-component reactions could be intercepted by a third component of one or more atoms, a new three-component transition metal-catalyzed cycloaddition is described. This new [5+2+1] cycloaddition proceeds in good to excellent yield and with high or complete regioselectivity with a variety of carbonyl-substituted alkynes to give bicyclo[3.3.0]octenone adducts, resulting from transannular closure of the intermediate eight-membered-ring cycloadduct. Effects of concentration, temperature, pressure, and catalyst loading on the efficiency of the reaction are discussed. This process provides access to complex building blocks for synthesis based on simple, readily available components.

    View details for DOI 10.1021/ja0176301

    View details for Web of Science ID 000174520500012

    View details for PubMedID 11902870

  • [(arene)Rh(cod)](+) complexes as catalysts for [5+2] cycloaddition reactions ANGEWANDTE CHEMIE-INTERNATIONAL EDITION Wender, P. A., Williams, T. J. 2002; 41 (23): 4550-?

    View details for Web of Science ID 000179752500035

    View details for PubMedID 12458535

  • Molecular transporters for peptides: delivery of a cardioprotective epsilon PKC agonist peptide into cells and intact ischemic heart using a transport system, R-7 CHEMISTRY & BIOLOGY Chen, L., Wright, L. R., Chen, C. H., Oliver, S. F., Wender, P. A., Mochly-Rosen, D. 2001; 8 (12): 1123-1129

    Abstract

    Recently, we reported a novel oligoguanidine transporter system, polyarginine (R(7)), which, when conjugated to spectroscopic probes (e.g., fluorescein) and drugs (e.g., cyclosporin A), results in highly water-soluble conjugates that rapidly enter cells and tissues. We report herein the preparation of the first R(7) peptide conjugates and a study of their cellular and organ uptake and functional activity. The octapeptide (psi)(epsilon)RACK was selected for this study as it is known to exhibit selective epsilon protein kinase C isozyme agonist activity and to reduce ischemia-induced damage in cardiomyocytes. However, (psi)(epsilon)RACK is not cell-permeable.Here we show that an R(7)-(psi)(epsilon)RACK conjugate readily enters cardiomyocytes, significantly outperforming (psi)(epsilon)RACK conjugates of the transporters derived from HIV Tat and from Antennapedia. Moreover, R(7)-(psi)(epsilon)RACK conjugate reduced ischemic damage when delivered into intact hearts either prior to or after the ischemic insult.Our data suggest that R(7) converts a peptide lead into a potential therapeutic agent for the ischemic heart.

    View details for Web of Science ID 000173750400001

    View details for PubMedID 11755391

  • An efficient, scalable synthesis of the molecular transporter octaarginine via a segment doubling strategy ORGANIC LETTERS Wender, P. A., Jessop, T. C., Pattabiraman, K., Pelkey, E. T., VanDeusen, C. L. 2001; 3 (21): 3229-3232

    Abstract

    [reaction: see text]. Short oligomers of arginine function as remarkably efficient molecular transporters of drugs and probe molecules into cells and tissue. Currently, these compounds are prepared on resin through a unidirectional solid-phase synthesis. To extend the utility of these compounds for therapeutic and research applications, a scalable solution-phase synthesis of Arg8 (1) has been developed on the basis of a segment doubling strategy that proceeds in 13 steps and 28% overall yield from 4, including a novel one-step perdeprotection-perguanidinylation reaction.

    View details for DOI 10.1021/ol0161108

    View details for Web of Science ID 000171708000001

    View details for PubMedID 11594801

  • Toward the identification of selective modulators of protein kinase C (PKC) isozymes: Establishment of a binding assay for PKC isozymes using synthetic C1 peptide receptors and identification of the critical residues involved in the phorbol ester binding BIOORGANIC & MEDICINAL CHEMISTRY Shindo, M., Irie, K., Nakahara, A., Ohigashi, H., Konishi, H., Kikkawa, U., Fukuda, H., Wender, P. A. 2001; 9 (8): 2073-2081

    Abstract

    Conventional and novel protein kinase C (PKC) isozymes contain two cysteine-rich C1 domains (C1A and C1B), both of which are candidate phorbol-12,13-dibutyrate (PDBu) binding sites. We previously synthesized C1 peptides (of approximately 50 residues) corresponding to all PKC isozymes and measured their PDBu binding affinity. While many of these peptide receptors exhibited PDBu affinities comparable to the respective complete isozyme, some of the C1A peptides could not be used because they undergo temperature dependent inactivation. This problem was however eliminated by 4 degrees C incubation or elongation of the 50-mer C1 peptides at both N- and C-termini to increase their folding efficiency and stability. These findings enabled us to determine the K(d)'s of PDBu for all PKC C1 peptides (except for theta-C1A) and establish the value of these peptides as readily available, stable, and easily handled surrogates of the individual isozymes. The resultant C1 peptide receptor library can be used to screen for new ligands with PKC isozyme and importantly C1 domain selectivity. Most of the C1 peptide receptors showed strong PDBu binding affinities with K(d)'s in the nanomolar range (0.45-7.4 nM). Two peptides (delta-C1A and theta-C1A) bound PDBu over 100-fold less tightly. To identify the residues that contribute to this affinity difference, several mutants of delta-C1A and theta-C1A were synthesized. Both the G9K mutant of delta-C1A and the P9K mutant of theta-C1A showed K(d)'s of 2-3 nM. This approach provides a useful procedure to determine the role of each C1 domain of the PKC isozymes by point mutation.

    View details for Web of Science ID 000170138400014

    View details for PubMedID 11504643

  • Asymmetric synthesis of the tricyclic core of NGF-inducing cyathane diterpenes via a transition-metal-catalyzed [5+2] cycloaddition ORGANIC LETTERS Wender, P. A., Bi, F. C., Brodney, M. A., Gosselin, F. 2001; 3 (13): 2105-2108

    Abstract

    [reaction: see text] A concise asymmetric synthesis of the tricyclic core of cyathane diterpenes is described, based on a novel transition-metal-catalyzed intramolecular [5 + 2] cycloaddition of ynone-vinylcyclopropane 10 (assembled from commercially available (S)-(-)-limonene), which proceeds in 90% yield with >95% selectivity. This strategy provides efficient access (14 steps and 13% overall yield) to potential analogues as well as precursors of nerve growth factor (NGF)-inducing diterpenes.

    View details for DOI 10.1021/ol0160699

    View details for Web of Science ID 000169487700036

    View details for PubMedID 11418060

  • The C4 hydroxyl group of phorbol esters is not necessary for protein kinase C binding BIOORGANIC & MEDICINAL CHEMISTRY LETTERS Tanaka, M., Irie, K., Nakagawa, Y., Nakamura, Y., Ohigashi, H., Wender, P. A. 2001; 11 (5): 719-722

    Abstract

    To investigate the role of the hydroxyl group at position 4 of the phorbol esters in protein kinase C (PKC) binding and function, 4beta-deoxy-phorbol-12,13-dibutyrate (4beta-deoxy-PDBu, 5a) and 4beta-deoxy-phorbol-13-acetate (6a) were synthesized from phorbol (1). The binding affinities of these 4beta-deoxy compounds (5a, 6a) to the 13 PKC isozyme C1 domains were quite similar to those of the corresponding 4beta-hydroxy compounds (4a, 4b), suggesting that the C4 hydroxyl group of phorbol esters is not necessary for PKC binding. Moreover, functional assays showed that 4beta-deoxy-PDBu (5a) exhibited biological activities (Epstein-Barr virus induction and superoxide generation) equally potent to those of PDBu (4a). These solution phase results differ from expectations based on the previously reported solid-phase structure of the complex of PKCdelta-C1B and phorbol-13-acetate (4b).

    View details for Web of Science ID 000167375700025

    View details for PubMedID 11266177

  • Photocleavage of DNA by 4 '-bromoacetophenone analogs ARCHIVES OF PHARMACAL RESEARCH Jeon, R., Wender, P. A. 2001; 24 (1): 39-43

    Abstract

    4'-Bromoacetophenone analogs, which are able to generate monophenyl radicals capable of hydrogen atom abstraction, were investigated as possible photoinducible DNA cleaving agents. The potential of 4'-bromoacetophenone as a possible new DNA cleaver is explored. Pyrrolecarboxatmid conjugated 4'-bromoacetophenones, in particular, DNA cleaving activity and sequence-selectivity on the contiguous AT base pair sites.

    View details for Web of Science ID 000167157200006

    View details for PubMedID 11235810

  • The first intermolecular transition metal-catalyzed [5+2] cycloadditions with simple, unactivated, vinylcyclopropanes JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Wender, P. A., Barzilay, C. M., Dyckman, A. J. 2001; 123 (1): 179-180

    View details for Web of Science ID 000166258800024

    View details for PubMedID 11273617

  • Serial [5+2]/[4+2] Cycloadditions: Facile, Preparative, Multi-Component Syntheses of Polycyclic Compounds from Simple, Readily Available Starting Materials This research was supported by grant CHE-9800445 from the National Science Foundation. The Stanford Graduate Fellowship (M.J.C.S. and G.G.G.) is gratefully acknowledged. Angewandte Chemie (International ed. in English) Wender, P. A., Gamber, G. G., Scanio, M. J. 2001; 40 (20): 3895-3897

    View details for PubMedID 11668567

  • Serial [5+2]/[4+2] cycloadditions: Facile, preparative, multi-component syntheses of polycyclic compounds from simple, readily available starting materials ANGEWANDTE CHEMIE-INTERNATIONAL EDITION Wender, P. A., Gamber, G. G., Scanio, M. J. 2001; 40 (20): 3895-?
  • Design and synthesis of new DNA photocleavers, 4 '-bromoacetophenone-pyrrolecarboxamide hybrid compounds ARCHIVES OF PHARMACAL RESEARCH Jeon, R., Wender, P. A. 2000; 23 (6): 585-588

    Abstract

    4-Bromoacetophenone-pyrrolecarboxamide conjugates were designed and synthesized as photoinducible DNA cleaving agents which can generate monophenyl radicals capable of causing the hydrogen atom abstraction which initiates the scission of DNA.

    View details for Web of Science ID 000166072700009

    View details for PubMedID 11156179

  • The design, synthesis, and evaluation of molecules that enable or enhance cellular uptake: Peptoid molecular transporters PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Wender, P. A., Mitchell, D. J., Pattabiraman, K., Pelkey, E. T., Steinman, L., Rothbard, J. B. 2000; 97 (24): 13003-13008

    Abstract

    Certain proteins contain subunits that enable their active translocation across the plasma membrane into cells. In the specific case of HIV-1, this subunit is the basic domain Tat(49-57) (RKKRRQRRR). To establish the optimal structural requirements for this translocation process, and thereby to develop improved molecular transporters that could deliver agents into cells, a series of analogues of Tat(49-57) were prepared and their cellular uptake into Jurkat cells was determined by flow cytometry. All truncated and alanine-substituted analogues exhibited diminished cellular uptake, suggesting that the cationic residues of Tat(49-57) play a principal role in its uptake. Charge alone, however, is insufficient for transport as oligomers of several cationic amino acids (histidine, lysine, and ornithine) are less effective than Tat(49-57) in cellular uptake. In contrast, a 9-mer of l-arginine (R9) was 20-fold more efficient than Tat(49-57) at cellular uptake as determined by Michaelis-Menton kinetic analysis. The d-arginine oligomer (r9) exhibited an even greater uptake rate enhancement (>100-fold). Collectively, these studies suggest that the guanidinium groups of Tat(49-57) play a greater role in facilitating cellular uptake than either charge or backbone structure. Based on this analysis, we designed and synthesized a class of polyguanidine peptoid derivatives. Remarkably, the subset of peptoid analogues containing a six-methylene spacer between the guanidine head group and backbone (N-hxg), exhibited significantly enhanced cellular uptake compared to Tat(49-57) and even to r9. Overall, a transporter has been developed that is superior to Tat(49-57), protease resistant, and more readily and economically prepared.

    View details for Web of Science ID 000165476300022

    View details for PubMedID 11087855

  • Conjugation of arginine oligomers to cyclosporin A facilitates topical delivery and inhibition of inflammation NATURE MEDICINE Rothbard, J. B., Garlington, S., Lin, Q., Kirschberg, T., Kreider, E., McGrane, P. L., Wender, P. A., Khavari, P. A. 2000; 6 (11): 1253-1257

    Abstract

    Many systemically effective drugs such as cyclosporin A are ineffective topically because of their poor penetration into skin. To surmount this problem, we conjugated a heptamer of arginine to cyclosporin A through a pH-sensitive linker to produce R7-CsA. In contrast to unmodified cyclosporin A, which fails to penetrate skin, topically applied R7-CsA was efficiently transported into cells in mouse and human skin. R7-CsA reached dermal T lymphocytes and inhibited cutaneous inflammation. These data establish a general strategy for enhancing delivery of poorly absorbed drugs across tissue barriers and provide a new topical approach to the treatment of inflammatory skin disorders.

    View details for Web of Science ID 000165114800033

    View details for PubMedID 11062537

  • Synthesis and tumor-promoting activities of 12-epi-phorbol-12, 13-dibutyrate BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY Irie, K., Nakahara, A., Ikawa, Y., Tanaka, M., Nakagawa, Y., Nakamura, Y., Ohigashi, H., Wender, P. A. 2000; 64 (11): 2429-2436

    Abstract

    12-Epi-phorbol-12,13-dibutyrate (1), the C12-epimer of the most frequently used phorbol ester probe, phorbol-12,13-dibutyrate (PDBu), has been synthesized from phorbol in 9 steps in order to investigate the structural requirements for tumor-promoting activity. Compound 1 showed about 100-fold weaker in vitro biological activities related to in vivo tumor promotion, Epstein-Barr virus early antigen (EBV-EA)-inducing ability, superoxide (O2-) generation-inducing ability, and binding to the protein kinase C (PKC) regulatory domain surrogate peptides. The results indicated that the beta-stereochemistry at position 12 of the phorbol skeleton is important for optimal activity. Binding selectivity to each PKC C1 domain of 1 was almost equal to that of PDBu.

    View details for Web of Science ID 000165615900020

    View details for PubMedID 11193412

  • Synthesis and PKC isozyme surrogate binding of indothiolactam-V, a new thioamide analogue of tumor promoting indolactam-V BIOORGANIC & MEDICINAL CHEMISTRY LETTERS Nakagawa, Y., Irie, K., Ohigashi, H., Hayashi, H., Wender, P. A. 2000; 10 (18): 2087-2090

    Abstract

    To investigate the role of the amide group of (-)-indolactam-V (1) on PKC binding, we synthesized (-)-indothiolactam-V (2), a new thioamide analogue of 1, by microbial conversion using Streptomyces blastmyceticum. Compounds 2 and 1 showed similar binding affinities to conventional PKCs but 2 had lower affinities to novel PKCs, suggesting that novel PKCs recognize amide modifications more effectively than conventional PKCs.

    View details for Web of Science ID 000089679900011

    View details for PubMedID 10999477

  • Synthesis and biological evaluation of a new class of bryostatin analogues: the role of the C20 substituent in protein kinase C binding TETRAHEDRON LETTERS Wender, P. A., Hinkle, K. W. 2000; 41 (35): 6725-6729
  • Transition metal-catalyzed [6+2] cycloadditions of 2-vinylcyclobutanones and alkenes: A new reaction for the synthesis of eight-membered rings JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Wender, P. A., Correa, A. G., Sato, Y., Sun, R. 2000; 122 (32): 7815-7816
  • Asymmetric total synthesis of (+)-aphanamol I based on the transition metal catalyzed [5+2] cycloaddition of allenes and vinylcyclopropanes ORGANIC LETTERS Wender, P. A., Zhang, L. 2000; 2 (15): 2323-2326

    Abstract

    A concise asymmetric total synthesis of (+)-aphanamol I is described, based on the transition metal catalyzed [5 + 2] allenyl-vinylcyclopropane cycloaddition. The key cycloaddition precursor is convergently assembled from (R)-(+)-limonene and cyclopropane diester through a novel decarboxylative dehydration reaction. The metal-catalyzed [5 + 2] cycloaddition of this precursor proceeds with complete chemo, endo/exo, and diastereoselectivity in 93% yield, representing an effective general route to bicyclo[5.3.0]decane derivatives.

    View details for Web of Science ID 000088346400037

    View details for PubMedID 10930274

  • A new and practical five-carbon component for metal-catalyzed [5+2] cycloadditions: Preparative scale syntheses of substituted cycloheptenones ORGANIC LETTERS Wender, P. A., Dyckman, A. J., Husfeld, C. O., Scanio, M. J. 2000; 2 (11): 1609-1611
  • Synthesis and biological evaluation of bryostatin analogues: the role of the A-ring TETRAHEDRON LETTERS Wender, P. A., Lippa, B. 2000; 41 (7): 1007-1011
  • A new and practical five-carbon component for metal-catalyzed Organic letters Wender, P. A., Dyckman, A. J., Husfeld, C. O., Scanio, M. J. 2000; 2 (11): 1609-11

    Abstract

    Described herein is an efficient preparative scale synthesis of 1-(2-methyoxyethoxy)-1-vinylcyclopropane and the investigation of the utility of this reagent as a new five-carbon component in metal-catalyzed [5 + 2] cycloadditions. A new cycloaddition procedure is also described that proceeds up to 12-fold faster and with 10-fold less catalyst than previously described, providing cycloheptenones in many cases in minutes and in isolated yields of 75-97%. The procedure is readily conducted on a small or large scale (up to 100 mmol thus far).

    View details for PubMedID 10841491

  • Bromoacetophenone-based photonucleases: Photoinduced cleavage of DNA by 4 '-bromoacetophenone-pyrrolecarboxamide conjugates ORGANIC LETTERS Wender, P. A., Jeon, R. 1999; 1 (13): 2117-2120

    Abstract

    [formula: see text] 4'-Bromoacetophenone derivatives which upon excitation can generate monophenyl radicals capable of hydrogen atom abstraction were investigated as photoinducible DNA cleaving agents. Pyrrolecarboxamide-conjugated 4'-bromoacetophenones were synthesized, and their DNA cleaving activities and sequence selectivities were determined.

    View details for Web of Science ID 000084980700020

    View details for PubMedID 10836065

  • Transition metal-catalyzed [5+2] cycloadditions of 2-substituted-1-vinylcyclopropanes: Catalyst control and reversal of regioselectivity ORGANIC LETTERS Wender, P. A., Dyckman, A. J. 1999; 1 (13): 2089-2092
  • Transition metal-catalyzed [5+2] cycloadditions with substituted cyclopropanes: First studies of regio- and stereoselectivity JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Wender, P. A., Dyckman, A. J., Husfeld, C. O., Kadereit, D., Love, J. A., Rieck, H. 1999; 121 (44): 10442-10443
  • A new class of simplified phorbol ester analogues: Synthesis and binding to PKC and eta PKC-C1B (eta PKC-CPD2) ORGANIC LETTERS Wender, P. A., Kirschberg, T. A., Williams, P. D., Bastiaans, H. M., Irie, K. 1999; 1 (7): 1009-1012

    Abstract

    [formula: see text] A unique class of simplified phorbol ester analogues is described for the first time. A highly efficient retro-annelation sequence was developed in order to remove the five-membered ring from the phorbol diterpene core, allowing access to BCD ring analogues of the phorbol esters. The binding of these analogues to protein kinase C (PKC) and the truncated peptide eta PKC-C1B (eta PKC-CRD2) is also reported.

    View details for Web of Science ID 000085171900013

    View details for PubMedID 10825954

  • Synthesis and phorbol ester-binding studies of the individual cysteine-rich motifs of protein kinase D BIOORGANIC & MEDICINAL CHEMISTRY LETTERS Irie, K., Nakahara, A., Ohigashi, H., Fukuda, H., Wender, P. A., Konishi, H., Kikkawa, U. 1999; 9 (17): 2487-2490

    Abstract

    To investigate the phorbol ester-binding properties of the individual cysteine-rich motifs of protein kinase D (PKD), the 52-mer peptides containing each cysteine-rich motif of PKD (PKD-C1A, PKD-C1B) have been synthesized. The [3H]phorbol-12,13-dibutyrate (PDBu) binding to PKD-C1A was affected drastically by incubation temperature while that to PKD-C1B was not. Scatchard analysis of [3H]PDBu binding to both PKD C1 peptides gave dissociation constants of 2.5 +/- 0.4 and 2.7 +/- 0.8 nM for PKD-C1A and PKD-C1B, respectively, indicating that the two cysteine-rich motifs of PKD are functionally equivalent like those of PKCgamma.

    View details for Web of Science ID 000082476300007

    View details for PubMedID 10498194

  • The rational design of potential chemotherapeutic agents: Synthesis of bryostatin analogues Wender, P. A., Hinkle, K. W., Koehler, M. F., Lippa, B. JOHN WILEY & SONS INC. 1999: 388-407

    Abstract

    The bryostatins are a unique family of cancer chemotherapeutic candidates isolated from marine bryozoa. While their molecular mode of action is not known, these macrolactones exhibit high affinities for protein kinase C (PKC) isozymes, compete for the phorbol ester binding site on PKC, and stimulate kinase activity in vitro and in vivo. Unlike the phorbol esters, they do not act as tumor promoters. Despite promising biological properties, the supply of these compounds is limited by the difficulty of their isolation from natural sources and their synthetic complexity. A new class of bryostatin analogues which retain the putative recognition domain of the bryostatins but are simplified through deletions and modifications in the C1-C14 spacer domain have been designed using computer models. A convergent synthesis has been realized for the production, in gram quantities, of these recognition and spacer domains whose coupling allows for the generation of a range of analogues. The final closure process involves a novel macrotransacetalization reaction which proceeds with complete stereoselectivity. The solution structures of two synthetic analogues were determined by NMR spectroscopy and found to be very similar to the previously reported structures of bryostatins 1 and 10. In addition, these structures appear to indicate that the stereochemistry of the C3 hydroxyl group plays a significant role in the conformation of the macrolactone. All analogues bound strongly to a mixture of PKC isozymes, and several exhibited significant levels of in vitro growth inhibitory activity against human cancer cell lines. Taken together, this work provides important steps toward the development and understanding of simplified, synthetically accessible analogues of the bryostatins as potential chemotherapeutic agents.

    View details for Web of Science ID 000082385200006

    View details for PubMedID 10502742

  • Rhodium-catalyzed [5+2] cycloadditions of allenes and vinylcyclopropanes: Asymmetric total synthesis of (+)-dictamnol ORGANIC LETTERS Wender, P. A., Fuji, M., Husfeld, C. O., Love, J. A. 1999; 1 (1): 137-139
  • Selective binding of bryostatin analogues to the cysteine rich domains of protein kinase C isozymes BIOORGANIC & MEDICINAL CHEMISTRY LETTERS Wender, P. A., Lippa, B., Park, C. M., Irie, K., Nakahara, A., Ohigashi, H. 1999; 9 (12): 1687-1690

    Abstract

    Designed bryostatin analogues are assayed for binding affinity to individual cysteine rich domains of several protein kinase C (PKC) isozymes. These analogues exhibit significant selectivity for the PKCdelta-C1B peptide in terms of absolute affinity and the PKCdelta-C1A peptide in terms of relative affinity when compared to phorbol-12,13-dibutyrate.

    View details for Web of Science ID 000080896500013

    View details for PubMedID 10397502

  • Transition metal-catalyzed [5+2] cycloadditions of allenes and vinylcyclopropanes: First studies of endo-exo selectivity, chemoselectivity, relative stereochemistry, and chirality transfer JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Wender, P. A., Glorius, F., Husfeld, C. O., Langkopf, E., Love, J. A. 1999; 121 (22): 5348-5349
  • Solid-phase synthesis, mass spectrometric analysis of the zinc-folding, and phorbol ester-binding studies of the 116-mer peptide containing the tandem cysteine-rich C1 domains of protein kinase C gamma BIOORGANIC & MEDICINAL CHEMISTRY Fukuda, H., Irie, K., Nakahara, A., Ohigashi, H., Wender, P. A. 1999; 7 (6): 1213-1221

    Abstract

    Tumor-promoting phorbol esters activate protein kinase C (PKC) isozymes by binding to the zinc-finger like cysteine-rich domains in the N-terminal regulatory region. Our recent studies have revealed that only PKCgamma has two high affinity phorbol ester-binding domains, providing a structural blueprint for the rational design of PKCgamma-selective modulators for the treatment of neuropathic pain. To extend this approach, the 116-mer peptide containing the double cysteine-rich motifs of PKCgamma (gamma-C1A-C1B) has been synthesized for the first time using an Fmoc-solid phase strategy with a stepwise chain elongation. This peptide was purified by the reversed phase HPLC to give satisfactory mass data (MALDI-TOF-MS and ESI-TOF-MS). The peptide was successfully folded by zinc treatment and the folded peptide was analyzed intact under neutral conditions by ESI-TOF-MS. The multiple charge mass envelopes shifted to those of the lower mass charge state by addition of 4 molar equiv. ZnCl2, suggesting that gamma-C1A-C1B preserves some higher order structure by the zinc folding. Moreover, the mass spectrum of the zinc-folded peptide in the presence of EDTA clearly showed that gamma-C1A-C1B coordinates exactly four atoms of zinc. This zinc stoichiometry is identical to that of native PKCgamma. Scatchard analysis of the zinc-folded peptide revealed two binding sites of distinctly different affinities (Kd=6.0 +/- 1.5 and 47.0 +/- 6.6 nM) comparable to those reported by Quest and Bell for the GST fusion protein of gamma-C1A-C1B prepared by DNA recombination. These results indicate that gamma-C1A-C1B serves as an effective surrogate for native PKCgamma for the study of the structural characteristics of the binding recognition event and the design, discovery, and development of new PKCgamma-selective modulators.

    View details for Web of Science ID 000081084000028

    View details for PubMedID 10428394

  • Mapping phorbol ester binding domains of protein kinase C (PKC): The design, synthesis and biological activity of novel phorbol ester dimers SYNTHESIS-STUTTGART Wender, P. A., Koehler, M. F., Wright, D. L., Irie, K. 1999: 1401-1406
  • Synthesis and biological evaluation of fully synthetic bryostatin analogues TETRAHEDRON LETTERS Wender, P. A., De Brabander, J., Harran, P. G., Hinkle, K. W., Lippa, B., Pettit, G. R. 1998; 39 (47): 8625-8628
  • The transition metal-catalyzed intermolecular [5+2] cycloaddition: The homologous Diels-Alder reaction JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Wender, P. A., Rieck, H., Fuji, M. 1998; 120 (42): 10976-10977
  • Synthesis and binding studies of the 116-mer peptide containing the double cysteine-rich motifs of protein kinase C gamma TETRAHEDRON LETTERS Fukuda, H., Irie, K., Nakahara, A., Oie, K., Ohigashi, H., Wender, P. A. 1998; 39 (43): 7943-7946
  • Molecular basis for protein kinase C isozyme-selective binding: The synthesis, folding, and phorbol ester binding of the cysteine-rich domains of all protein kinase C isozymes JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Irie, K., Oie, K., Nakahara, A., Yanai, Y., Ohigashi, H., Wender, P. A., Fukuda, H., Konishi, H., Kikkawa, U. 1998; 120 (36): 9159-9167
  • The first metal-catalyzed intramolecular [5+2] cycloadditions of vinylcyclopropanes and alkenes: Scope, stereochemistry, and asymmetric catalysis TETRAHEDRON Wender, P. A., Husfeld, C. O., Langkopf, E., Love, J. A., Pleuss, N. 1998; 54 (25): 7203-7220
  • The design, computer modeling, solution structure, and biological evaluation of synthetic analogs of bryostatin 1 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Wender, P. A., Debrabander, J., Harran, P. G., Jimenez, J. M., Koehler, M. F., Lippa, B., Park, C. M., Siedenbiedel, C., Pettit, G. R. 1998; 95 (12): 6624-6629

    Abstract

    The bryostatins are a unique family of emerging cancer chemotherapeutic candidates isolated from marine bryozoa. Although the biochemical basis for their therapeutic activity is not known, these macrolactones exhibit high affinities for protein kinase C (PKC) isozymes, compete for the phorbol ester binding site on PKC, and stimulate kinase activity in vitro and in vivo. Unlike the phorbol esters, they are not first-stage tumor promoters. The design, computer modeling, NMR solution structure, PKC binding, and functional assays of a unique class of synthetic bryostatin analogs are described. These analogs (7b, 7c, and 8) retain the putative recognition domain of the bryostatins but are simplified through deletions and modifications in the C4-C14 spacer domain. Computer modeling of an analog prototype (7a) indicates that it exists preferentially in two distinct conformational classes, one in close agreement with the crystal structure of bryostatin 1. The solution structure of synthetic analog 7c was determined by NMR spectroscopy and found to be very similar to the previously reported structures of bryostatins 1 and 10. Analogs 7b, 7c, and 8 bound strongly to PKC isozymes with Ki = 297, 3.4, and 8.3 nM, respectively. Control 7d, like the corresponding bryostatin derivative, exhibited weak PKC affinity, as did the derivative, 9, lacking the spacer domain. Like bryostatin, acetal 7c exhibited significant levels of in vitro growth inhibitory activity (1.8-170 ng/ml) against several human cancer cell lines, providing an important step toward the development of simplified, synthetically accessible analogs of the bryostatins.

    View details for Web of Science ID 000074131900012

    View details for PubMedID 9618462

  • Synthesis of the first members of a new class of biologically active bryostatin analogues JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Wender, P. A., De Brabander, J., Harran, P. G., Jimenez, J. M., Koehler, M. F., Lippa, B., Park, C. M., Shiozaki, M. 1998; 120 (18): 4534-4535
  • First studies of the transition metal-catalyzed [5+2] cycloadditions of alkenes and vinylcyclopropanes: Scope and stereochemistry JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Wender, P. A., Husfeld, C. O., Langkopf, E., Love, J. A. 1998; 120 (8): 1940-1941
  • Comparison of chemical characteristics of the first and the second cysteine-rich domains of protein kinase C gamma BIOORGANIC & MEDICINAL CHEMISTRY Irie, K., Yanai, Y., Oie, K., Ishizawa, J., Nakagawa, Y., Ohigashi, H., Wender, P. A., Kikkawa, U. 1997; 5 (8): 1725-1737

    Abstract

    Protein kinase C (PKC) is a key enzyme family involved in cellular signal transduction. The binding of endogenous diacyl glycerol (DAG) to the cysteine-rich domain (CRD) of PKC is associated with normal cell signaling and function. In contrast, the binding of exogenous phorbol esters to the CRD of PKC is considered to be a key initiating event in tumor promotion. Conventional PKC isozymes (PKC alpha, beta I, beta II, and gamma) contain two CRDs, both of which are candidates for the phorbol ester binding site. In order to elucidate the binding requirements of phorbol esters and to obtain information on the phorbol ester binding site in native PKC gamma, several key chemical characteristics of the first and the second CRDs consisting of ca. 50 amino acids of rat PKC gamma (gamma-CRD1 and gamma-CRD2) were examined. In the presence of Zn2+ and phosphatidylserine (PS), both CRDs gave similar Kd values (65.3 nM for gamma-CRD1, 44.1 nM for gamma-CRD2) in phorbol 12,13-dibutyrate (PDBu) binding assays. In comparison, the binding affinity of PDBu for native rat PKC gamma was found to be 6.8 nM. Zn2+ was shown to play an important role in the folding and PDBu binding of both CRDs. A Zn(2+)-induced conformational change was observed for the first time by CD spectroscopic analysis of the complexed and uncomplexed CRDs. Relative to the pronounced Zn2+ effect, most divalent first row transition metal ions along with Ca2+, Mg2+, and Al3+ were ineffective in folding either CRD. Notably, however, Co2+ exhibited a gamma-CRD1-selective effect, suggesting that metal ions, not unlike extensively used organic probes, might also become effective tools for controlling isozyme selective activation of PKC. Moreover, group Ib (Cu2+ and Ag+) and group IIb element ions other than Zn2+ (Cd2+ and Hg2+) were found to abolish PDBu binding of both CRDs. Importantly, these inhibitory effects of Cu2+, Ag+, and Cd2+, and Hg2+ were also observed with native PKC gamma. These results indicate that recent reports on the modulation of conventional PKC by heavy metal ions could be explained by their coordination to the CRDs. While the similar affinities of gamma-CRD1 and gamma-CRD2 for PDBu suggest that either site qualifies as the PDBu binding site, new molecular probes of these CRD3 have now been identified that provide information on the preferred site. These novel ligands (5a and 5b) were synthesized by aza-Claisen rearrangement of (-)-N13-desmethyl-N13-allylindolactam-G (4). These compounds did not significantly affect the specific PDBu binding of gamma-CRD1 but did inhibit that of gamma-CRD2 with similar potency to (-)-indolactam-V. Moreover, these new probes did not significantly inhibit the PDBu binding of native PKC gamma. (-)-Indolactam-V itself bound almost equally to gamma-CRD1, gamma-CRD2, and native PKC gamma. These results suggest that the major PDBu binding site in native PKC gamma is the first CRD, not the second CRD, unlike the novel PKCs.

    View details for Web of Science ID A1997XX51600022

    View details for PubMedID 9313873

  • Protein kinase C regulatory domain surrogate peptides: Effects of metal ions on folding, phorbol ester-binding, and selectivity BIOORGANIC & MEDICINAL CHEMISTRY LETTERS Irie, K., Yanai, Y., Oie, K., Ohigashi, H., Wender, P. A. 1997; 7 (8): 965-970
  • The pinene path to taxanes .6. A concise stereocontrolled synthesis of taxol JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Wender, P. A., Badham, N. F., Conway, S. P., Floreancig, P. E., Glass, T. E., HOUZE, J. B., Krauss, N. E., Lee, D. S., Marquess, D. G., McGrane, P. L., Meng, W., Natchus, M. G., Shuker, A. J., Sutton, J. C., Taylor, R. E. 1997; 119 (11): 2757-2758
  • The pinene path to taxanes .5. Stereocontrolled synthesis of a versatile taxane precursor JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Wender, P. A., Badham, N. F., Conway, S. P., Floreancig, P. E., Glass, T. E., Granicher, C., HOUZE, J. B., Janichen, J., Lee, D. S., Marquess, D. G., McGrane, P. L., Meng, W., MUCCIARO, T. P., Muhlebach, M., Natchus, M. G., Paulsen, H., Rawlins, D. B., Satkofsky, J., Shuker, A. J., Sutton, J. C., Taylor, R. E., Tomooka, K. 1997; 119 (11): 2755-2756
  • Synthesis and characterization of the first cysteine-rich domain of novel protein kinase C BIOORGANIC & MEDICINAL CHEMISTRY LETTERS Yanai, Y., Irie, K., Ohigashi, H., Wender, P. A. 1997; 7 (2): 117-122
  • Sequence-specific DNA cleavage by conjugates ofbenzotriazoles and minor groove binders. JACS Wender PA., Touami SM, Poon CC 1997: 7611-7612.
  • The first formal asymmetric synthesis of phorbol. JACS Wender PA, Rice KD, Schnute ME. 1997: 7987-7898
  • The pinene path to taxanes .6. A concise stereocontrolled synthesis of taxol. JACS Wender PA, Badham NF, Conway SP, Floreancig PE, Glass TE, Houze JB, Krauss NE, Lee DS, Marquess DG, McGrane PL, Meng W. 1997: 2757-2758.
  • The first synthesis of a daphnane diterpene: the enantiocontrolled total synthesis of (+)-resiniferatoxin. JACS Wender PA, Jesudason CD, Nakahira H, Tamura N, Tebbe AL, Ueno Y. 1997: 12976-12977.
  • Synthesis and biological activities of new conformationally restricted analogues of (-)-indolactam-V: Elucidation of the biologically active conformation of the tumor-promoting teleocidins JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Irie, K., Isaka, T., Iwata, Y., Yanai, Y., Nakamura, Y., Koizumi, F., Ohigashi, H., Wender, P. A., Satomi, Y., Nishino, H. 1996; 118 (44): 10733-10743
  • Synthesis and characterization of new photolabile phorbol esters for affinity labeling of protein kinase C JOURNAL OF ORGANIC CHEMISTRY Irie, K., Ishii, T., Ohigashi, H., Wender, P. A., Miller, B. L., Takeda, N. 1996; 61 (6): 2164-2173
  • Synthesis and characterization of the second cysteine-rich region of mouse skin PKC eta BIOORGANIC & MEDICINAL CHEMISTRY LETTERS Irie, K., Yanai, Y., Ohigashi, H., Wender, P. A., Miller, B. L. 1996; 6 (4): 353-356
  • The Pinene Path to Taxanes. 4. Approaches to Taxol and Taxol Analogs through Elaboration of Aromatic C-Ring Precursors. The Journal of organic chemistry Wender, P. A., Glass, T. E., Krauss, N. E., MŘhlebach, M., Peschke, B., Rawlins, D. B. 1996; 61 (22): 7662-7663

    View details for PubMedID 11667717

  • Introduction: Frontiers in Organic Synthesis. Chemical reviews Wender, P. A. 1996; 96 (1): 1-2

    View details for PubMedID 11848741

  • SYNTHESIS AND BIOLOGICAL-ACTIVITIES OF NEW CONFORMATIONALLY FIXED ANALOGS OF (-)-INDOLACTAM-V, THE CORE STRUCTURE OF TUMOR-PROMOTING TELEOCIDINS BIOORGANIC & MEDICINAL CHEMISTRY LETTERS Irie, K., Koizumi, F., Iwata, Y., Ishii, T., Yanai, Y., Nakamura, Y., Ohigashi, H., Wender, P. A. 1995; 5 (5): 453-458
  • THE INTRAMOLECULAR ADDITION OF SILYLATED ALKYNES TO ALDEHYDES - METHODOLOGY FOR THE CONSTRUCTION OF CYCLIC ENEDIYNES AND ITS APPLICATION TO DYNEMICIN ANALOGS TETRAHEDRON LETTERS Wender, P. A., Beckham, S., Mohler, D. L. 1995; 36 (2): 209-212
  • IDENTIFICATION, ACTIVITY, AND STRUCTURAL STUDIES OF PEPTIDES INCORPORATING THE PHORBOL ESTER-BINDING DOMAIN OF PROTEIN-KINASE-C PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Wender, P. A., Irie, K., Miller, B. L. 1995; 92 (1): 239-243

    Abstract

    The family of homologous enzymes known as protein kinase C (PKC) has been the object of intense interest because of its crucial role in cellular signal transduction. Although considerable information about the activation of PKC has been gained through structure-activity, molecular modeling, and synthetic studies of both natural and designed activators, information about the structure of PKC itself has been limited by its large size and requirement for phospholipid cofactors. Additionally, difficulties in the purification of truncated mutants of PKC have thus far prevented their analysis by nuclear magnetic resonance (NMR) or x-ray crystallographic methods. We describe the identification, synthesis, ligand-binding analysis, cofactor requirements, and preliminary NMR evaluation of two subdomains (peptides B and C) of the regulatory domain of PKC-gamma. Peptides B and C bind [3H]phorbol 12,13-dibutyrate with good affinity (Kd = 6.4 microM and 414 nM, respectively) in the presence of phosphatidylserine. In comparison, the binding affinity of [3H]phorbol 12,13-dibutyrate for PKC was found to be 2.6 nM. Like PKC itself, these peptides also recognize other PKC activators, including dioctanoylglycerol and teleocidin B-4, and exhibit an ability to differentiate phorbol ester from its C-4 epimer. NMR studies of PKC subdomains are also described, indicating that both peptides B and C are well behaved in solution and do not exhibit any concentration-dependent changes. Finally, these studies reveal that peptide B becomes conformationally ordered only in the presence of phospholipid, suggesting that the regulatory domain of PKC itself might be organized for activation only when associated with the lipid bilayer, where its activator (diacylglycerol) is encountered.

    View details for Web of Science ID A1995QB23800049

    View details for PubMedID 7816824

  • A 2ND-GENERATION PHOTOCHEMICALLY ACTIVATABLE DYNEMICIN ANALOG - A CONCISE SYNTHESIS AND DNA CLEAVAGE STUDIES SYNTHESIS-STUTTGART Wender, P. A., Beckham, S., OLEARY, J. G. 1994: 1278-1282
  • STUDIES ON DNA-CLEAVING AGENTS - COMPUTER MODELING ANALYSIS OF THE MECHANISM OF ACTIVATION AND CLEAVAGE OF DYNEMICIN OLIGONUCLEOTIDE COMPLEXES PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Wender, P. A., Kelly, R. C., Beckham, S., Miller, B. L. 1991; 88 (19): 8835-8839

    Abstract

    Dynemicin A is a recently identified antitumor antibiotic. Upon activation, dynemicin is reported to cause double-stranded cleavage of DNA, putatively through the intermediacy of a diradical. Computer modeling of this activation and cleavage process is described herein as part of an effort to establish a structural hypothesis for this mechanistic sequence and for the design of simple analogues. Intercalation complexes of duplex dodecamers [d(CGCGAATTCGCG)]2 and [d(GC)6]2 with both enantiomers of dynemicin and of all related mechanistic intermediates are evaluated. Examination of these structures shows that cycloaromatization of dynemicin to a diradical intermediate results in the rotation of the diradical-forming subunit with respect to the intercalation plane that is of an opposite sense for the two dynemicin enantiomers. In addition, the activation of the (2S) enantiomer of dynemicin occurs by a less restricted approach trajectory than the corresponding (2R) enantiomer. In all complexes, the 5'-3' strand is at least 1 A closer than the 3'-5' strand to the diyl intermediate. As a result, complexes are produced in which the diyl moiety is aligned along [(2S)] or across [(2R)] the minor groove, leading to different predictions for the selectivity of radical-initiated, oxidative lesion of DNA. Molecular dynamics simulations are found to support these predictions, including the 3-base-pair offset cleavage reported for dynemicin.

    View details for Web of Science ID A1991GH80500114

    View details for PubMedID 1924343

  • MODELING OF THE BRYOSTATINS TO THE PHORBOL ESTER PHARMACOPHORE ON PROTEIN KINASE-C PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Wender, P. A., CRIBBS, C. M., Koehler, K. F., Sharkey, N. A., Herald, C. L., Kamano, Y., Pettit, G. R., Blumberg, P. M. 1988; 85 (19): 7197-7201

    Abstract

    The bryostatins are macrocyclic lactones that represent an additional structural class of potent activators of protein kinase C. These marine animal biosynthetic products are of unusual interest because they induce only a subset of the biological responses induced by the phorbol esters. We have now determined the binding affinities of naturally occurring and semisynthetic bryostatins for protein kinase C by competition analysis with [26-3H]bryostatin 4 as the radioactive ligand. Esterification of the hydroxyl group at C26 caused dramatic loss of activity as did inversion of the asymmetric center at this position. In contrast, neither of the ester groups at C7 and C20 had a major influence on activity. Computer modeling of the phorbol esters, related diterpenes, and indole alkaloids suggested that the C20, C9, and C4 oxygens of phorbol represented critical elements of the phorbol ester pharmacophore. The C26 oxygen of the bryostatins, together with the C1 and C19 oxygens, gave an excellent spatial correlation with this model, with a root-mean-square deviation of 0.16 A (compared to 0.10-0.35 A among phorbol-related diterpenes). The extension of the phorbol ester pharmacophore model to the bryostatins and its agreement with the structure-activity relations for the bryostatin class of compounds provide additional support for the validity of the model.

    View details for Web of Science ID A1988Q358500033

    View details for PubMedID 3174627

  • ANALYSIS OF THE PHORBOL ESTER PHARMACOPHORE ON PROTEIN-KINASE-C AS A GUIDE TO THE RATIONAL DESIGN OF NEW CLASSES OF ANALOGS PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Wender, P. A., Koehler, K. F., Sharkey, N. A., DELLAQUILA, M. L., Blumberg, P. M. 1986; 83 (12): 4214-4218

    Abstract

    The diterpene diester phorbol 12-myristate 13-acetate and the alkaloid teleocidin B are structurally unrelated natural products that display similar potent irritant and tumor-promoting activities. Computer modeling of these and other structural classes of tumor promoters show a marked similarity in the relative positions of certain heteroatoms and hydrophobic groups. For phorbol this mapping consists of the C-4, C-9, and C-20 hydroxyl groups as well as a hydrophobic region filled by a long-chain acyl functionality attached to either the C-12 or the C-13 positions. Diacylglycerols, thought to be the endogenous activators of the major phorbol ester receptor protein kinase C likewise fit this model in a stereospecific fashion. As an initial test of the utility of the model, members of a new and simplified class of activators were synthesized that possess the predicted essential structural features. These compounds all inhibited specific phorbol ester binding to protein kinase C, albeit with low affinity (10-60 microM); further analysis of one derivative, decylhydroxylindole, confirmed that the inhibition of phorbol ester binding was competitive. This same derivative inhibited epidermal growth factor binding in intact Swiss 3T3 cells and studies with another derivative showed phosphorylation of a 40-kDa protein in platelets. Both of these in vivo responses are characteristic of phorbol esters.

    View details for Web of Science ID A1986C835000023

    View details for PubMedID 3086877

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