Paul A. Wender

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Name: Wender, Paul A.

Organization: Stanford University , USA

Department: Departments of Chemistry and of Chemical and Systems Biology

Title: (PhD)

TOPICS

Analytical Chemistry

Organic Chemistry

allene

Chemicals
References

Ynol Ethers as Ketene Equivalents in Rhodium-Catalyzed Intermolecular [5 + 2] Cycloaddition Reactions

Co-reporter:Paul A. Wender, Christian Ebner, Brandon D. Fennell, Fuyuhiko Inagaki, and Birte Schröder

Organic Letters November 3, 2017 Volume 19(Issue 21) pp:5810-5810

Publication Date(Web):October 16, 2017

DOI:10.1021/acs.orglett.7b02765

The previously unexplored metal-catalyzed [5 + 2] cycloadditions of vinylcyclopropanes (VCPs) and electron-rich alkynes (ynol ethers) have been found to provide a highly efficient, direct route to dioxygenated seven-membered rings, a common feature of numerous natural and non-natural targets and building blocks for synthesis. The reactions proceed in high yield at room temperature and tolerate a broad range of functionalities. Substituted VCPs were found to react with high regioselectivity.

Vault Nanoparticles: Chemical Modifications for Imaging and Enhanced Delivery

Co-reporter:Nancy L. Benner, Xiaoyu Zang, Daniel C. Buehler, Valerie A. Kickhoefer, Michael E. Rome, Leonard H. Rome, and Paul A. Wender

ACS Nano 2017 Volume 11(Issue 1) pp:

Publication Date(Web):December 28, 2016

DOI:10.1021/acsnano.6b07440

Vault nanoparticles represent promising vehicles for drug and probe delivery. Innately found within human cells, vaults are stable, biocompatible nanocapsules possessing an internal volume that can encapsulate hundreds to thousands of molecules. They can also be targeted. Unlike most nanoparticles, vaults are nonimmunogenic and monodispersed and can be rapidly produced in insect cells. Efforts to create vaults with modified properties have been, to date, almost entirely limited to recombinant bioengineering approaches. Here we report a systematic chemical study of covalent vault modifications, directed at tuning vault properties for research and clinical applications, such as imaging, targeted delivery, and enhanced cellular uptake. As supra-macromolecular structures, vaults contain thousands of derivatizable amino acid side chains. This study is focused on establishing the comparative selectivity and efficiency of chemically modifying vault lysine and cysteine residues, using Michael additions, nucleophilic substitutions, and disulfide exchange reactions. We also report a strategy that converts the more abundant vault lysine residues to readily functionalizable thiol terminated side chains through treatment with 2-iminothiolane (Traut’s reagent). These studies provide a method to doubly modify vaults with cell penetrating peptides and imaging agents, allowing for in vitro studies on their enhanced uptake into cells.Keywords: cell-penetrating transporter; chemical modification; imaging; nanoparticle; protein cage; vaults;

Charge-altering releasable transporters (CARTs) for the delivery and release of mRNA in living animals

Co-reporter:Colin J. McKinlay;Jessica R. Vargas;Timothy R. Blake;Jonathan W. Hardy;Masamitsu Kanada;Christopher H. Contag;Robert M. Waymouth

PNAS 2017 Volume 114 (Issue 4 ) pp:E448-E456

Publication Date(Web):2017-01-24

DOI:10.1073/pnas.1614193114

Functional delivery of mRNA to tissues in the body is key to implementing fundamentally new and potentially transformative strategies for vaccination, protein replacement therapy, and genome editing, collectively affecting approaches for the prevention, detection, and treatment of disease. Broadly applicable tools for the efficient delivery of mRNA into cultured cells would advance many areas of research, and effective and safe in vivo mRNA delivery could fundamentally transform clinical practice. Here we report the step-economical synthesis and evaluation of a tunable and effective class of synthetic biodegradable materials: charge-altering releasable transporters (CARTs) for mRNA delivery into cells. CARTs are structurally unique and operate through an unprecedented mechanism, serving initially as oligo(α-amino ester) cations that complex, protect, and deliver mRNA and then change physical properties through a degradative, charge-neutralizing intramolecular rearrangement, leading to intracellular release of functional mRNA and highly efficient protein translation. With demonstrated utility in both cultured cells and animals, this mRNA delivery technology should be broadly applicable to numerous research and therapeutic applications.

Cell-Penetrating, Guanidinium-Rich Oligophosphoesters: Effective and Versatile Molecular Transporters for Drug and Probe Delivery

Co-reporter:Colin J. McKinlay; Robert M. Waymouth

Journal of the American Chemical Society 2016 Volume 138(Issue 10) pp:3510-3517

Publication Date(Web):February 22, 2016

DOI:10.1021/jacs.5b13452

The design, synthesis, and biological evaluation of a new family of highly effective cell-penetrating molecular transporters, guanidinium-rich oligophosphoesters, are described. These unique transporters are synthesized in two steps, irrespective of oligomer length, by the organocatalytic ring-opening polymerization (OROP) of 5-membered cyclic phospholane monomers followed by oligomer deprotection. Varying the initiating alcohol results in a wide variety of cargo attachment strategies for releasable or nonreleasable transporter applications. Initiation of oligomerization with a fluorescent probe produces, upon deprotection, a transporter-probe conjugate that is shown to readily enter multiple cell lines in a dose-dependent manner. These new transporters are superior in cell uptake to previously studied guanidinium-rich oligocarbonates and oligoarginines, showing over 2-fold higher uptake than the former and 6-fold higher uptake than the latter. Initiation with a protected thiol gives, upon deprotection, thiol-terminated transporters which can be thiol-click conjugated to a variety of probes, drugs and other cargos as exemplified by the conjugation and delivery of the model probe fluorescein-maleimide and the medicinal agent paclitaxel (PTX) into cells. Of particular significance given that drug resistance is a major cause of chemotherapy failure, the PTX-transporter conjugate, designed to evade Pgp export and release free PTX after cell entry, shows efficacy against PTX-resistant ovarian cancer cells. Collectively this study introduces a new and highly effective class of guanidinium-rich cell-penetrating transporters and methodology for their single-step conjugation to drugs and probes, and demonstrates that the resulting drug/probe-conjugates readily enter cells, outperforming previously reported guanidinium-rich oligocarbonates and peptide transporters.

Bioorthogonal Catalysis: A General Method To Evaluate Metal-Catalyzed Reactions in Real Time in Living Systems Using a Cellular Luciferase Reporter System

Co-reporter:Hsiao-Tieh Hsu, Brian M. Trantow, Robert M. Waymouth, and Paul A. Wender

Bioconjugate Chemistry 2016 Volume 27(Issue 2) pp:376

Publication Date(Web):September 14, 2015

DOI:10.1021/acs.bioconjchem.5b00469

The development of abiological catalysts that can function in biological systems is an emerging subject of importance with significant ramifications in synthetic chemistry and the life sciences. Herein we report a biocompatible ruthenium complex [Cp(MQA)Ru(C3H5)]+PF6– 2 (Cp = cyclopentadienyl, MQA = 4-methoxyquinoline-2-carboxylate) and a general analytical method for evaluating its performance in real time based on a luciferase reporter system amenable to high throughput screening in cells and by extension to evaluation in luciferase transgenic animals. Precatalyst 2 activates alloc-protected aminoluciferin 4b, a bioluminescence pro-probe, and releases the active luminophore, aminoluciferin (4a), in the presence of luciferase-transfected cells. The formation and enzymatic turnover of 4a, an overall process selected because it emulates pro-drug activation and drug turnover by an intracellular target, is evaluated in real time by photon counting as 4a is converted by intracellular luciferase to oxyaminoluciferin and light. Interestingly, while the catalytic conversion (activation) of 4b to 4a in water produces multiple products, the presence of biological nucleophiles such as thiols prevents byproduct formation and provides almost exclusively luminophore 4a. Our studies show that precatalyst 2 activates 4b extracellularly, exhibits low toxicity at concentrations relevant to catalysis, and is comparably effective in two different cell lines. This proof of concept study shows that precatalyst 2 is a promising lead for bioorthogonal catalytic activation of pro-probes and, by analogy, similarly activatable pro-drugs. More generally, this study provides an analytical method to measure abiological catalytic activation of pro-probes and, by analogy with our earlier studies on pro-Taxol, similarly activatable pro-drugs in real time using a coupled biological catalyst that mediates a bioluminescent readout, providing tools for the study of imaging signal amplification and of targeted therapy.

Inhibition of Chikungunya Virus-Induced Cell Death by Salicylate-Derived Bryostatin Analogues Provides Additional Evidence for a PKC-Independent Pathway

Co-reporter:Daryl Staveness; Rana Abdelnabi; Katherine E. Near; Yu Nakagawa; Johan Neyts; Leen Delang; Pieter Leyssen

Journal of Natural Products 2016 Volume 79(Issue 4) pp:680-684

Publication Date(Web):February 22, 2016

DOI:10.1021/acs.jnatprod.5b01017

Chikungunya virus (CHIKV) has been spreading rapidly, with over one million confirmed or suspected cases in the Americas since late 2013. Infection with CHIKV causes devastating arthritic and arthralgic symptoms. Currently, there is no therapy to treat this disease, and the only medications focus on relief of symptoms. Recently, protein kinase C (PKC) modulators have been reported to inhibit CHIKV-induced cell death in cell assays. The salicylate-derived bryostatin analogues described here are structurally simplified PKC modulators that are more synthetically accessible than the natural product bryostatin 1, a PKC modulator and clinical lead for the treatment of cancer, Alzheimer’s disease, and HIV eradication. Evaluation of the anti-CHIKV activity of these salicylate-derived bryostatin analogues in cell culture indicates that they are among the most potent cell-protective agents reported to date. Given that they are more accessible and significantly more active than the parent natural product, they represent new therapeutic leads for controlling CHIKV infection. Significantly, these analogues also provide evidence for the involvement of a PKC-independent pathway. This adds a fundamentally distinct aspect to the importance or involvement of PKC modulation in inhibition of chikungunya virus replication, a topic of recent and growing interest.

Simplified Bryostatin Analogues Protect Cells from Chikungunya Virus-Induced Cell Death

Co-reporter:Daryl Staveness; Rana Abdelnabi; Adam J. Schrier; Brian A. Loy; Vishal A. Verma; Brian A. DeChristopher; Katherine E. Near; Johan Neyts; Leen Delang; Pieter Leyssen

Journal of Natural Products 2016 Volume 79(Issue 4) pp:675-679

Publication Date(Web):February 22, 2016

DOI:10.1021/acs.jnatprod.5b01016

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus showing a recent resurgence and rapid spread worldwide. While vaccines are under development, there are currently no therapies to treat this disease, except for over-the-counter (OTC) analgesics, which alleviate the devastating arthritic and arthralgic symptoms. To identify novel inhibitors of the virus, analogues of the natural product bryostatin 1, a clinical lead for the treatment of cancer, Alzheimer’s disease, and HIV eradication, were investigated for in vitro antiviral activity and were found to be among the most potent inhibitors of CHIKV replication reported to date. Bryostatin-based therapeutic efforts and even recent anti-CHIKV strategies have centered on modulation of protein kinase C (PKC). Intriguingly, while the C ring of bryostatin primarily drives interactions with PKC, A- and B-ring functionality in these analogues has a significant effect on the observed cell-protective activity. Significantly, bryostatin 1 itself, a potent pan-PKC modulator, is inactive in these assays. These new findings indicate that the observed anti-CHIKV activity is not solely mediated by PKC modulation, suggesting possible as yet unidentified targets for CHIKV therapeutic intervention. The high potency and low toxicity of these bryologs make them promising new leads for the development of a CHIKV treatment.

Function through Synthesis-Informed Design

Co-reporter:Paul A. Wender, Ryan V. Quiroz, and Matthew C. Stevens

Accounts of Chemical Research 2015 Volume 48(Issue 3) pp:752

Publication Date(Web):March 5, 2015

DOI:10.1021/acs.accounts.5b00004

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.

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

Co-reporter:Brian A. Loy; Adam B. Lesser; Daryl Staveness; Kelvin L. Billingsley; Lynette Cegelski

Journal of the American Chemical Society 2015 Volume 137(Issue 10) pp:3678-3685

Publication Date(Web):February 24, 2015

DOI:10.1021/jacs.5b00886

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.

Tetramethyleneethane Equivalents: Recursive Reagents for Serialized Cycloadditions

Co-reporter:Paul A. Wender; Matthew S. Jeffreys;Andrew G. Raub

Journal of the American Chemical Society 2015 Volume 137(Issue 28) pp:9088-9093

Publication Date(Web):May 11, 2015

DOI:10.1021/jacs.5b04091

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.

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

Co-reporter:Thomas J. L. Mustard, Paul A. Wender, and Paul Ha-Yeon Cheong

ACS Catalysis 2015 Volume 5(Issue 3) pp:1758

Publication Date(Web):January 27, 2015

DOI:10.1021/cs501828e

The origins of differential catalytic reactivities of four Rh(I) catalysts and their derivatives in the (5 + 2) cycloaddition reaction were elucidated using density functional theory. Computed free energy spans are in excellent agreement with known experimental rates. For every catalyst, the substrate geometries in the transition state remained constant (<0.1 Å RMSD for atoms involved in bond-making and -breaking processes). Catalytic efficiency is shown to be a function of how well the catalyst accommodates the substrate transition state geometry and electronics. This shows that the induced fit model for explaining biological catalysis may be relevant to transition metal catalysis. This could serve as a general model for understanding the origins of efficiencies of catalytic reactions.Keywords: catalysis; computations; DFT; ligands; NHC; organometallic; phosphine; rhodium; theory; transition metals

Guanidinium-Rich, Glycerol-Derived Oligocarbonates: A New Class of Cell-Penetrating Molecular Transporters That Complex, Deliver, and Release siRNA

Co-reporter:Paul A. Wender; Melanie A. Huttner; Daryl Staveness; Jessica R. Vargas;Adele F. Xu

Molecular Pharmaceutics 2015 Volume 12(Issue 3) pp:742-750

Publication Date(Web):January 14, 2015

DOI:10.1021/mp500581r

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.

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

Co-reporter:Xin Hong ; Matthew C. Stevens ; Peng Liu ; Paul A. Wender ;K. N. Houk

Journal of the American Chemical Society 2014 Volume 136(Issue 49) pp:17273-17283

Publication Date(Web):November 7, 2014

DOI:10.1021/ja5098308

Allenes are important 2π 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−π* backdonation. At the same time, insertion of the internal double bond of an allene-yne has a higher barrier as it would break π 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.

Toward the ideal synthesis and molecular function through synthesis-informed design

Co-reporter:Paul A. Wender

Natural Product Reports 2014 vol. 31(Issue 4) pp:433-440

Publication Date(Web):03 Mar 2014

DOI:10.1039/C4NP00013G

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.

Improved Protein Kinase C Affinity through Final Step Diversification of a Simplified Salicylate-Derived Bryostatin Analog Scaffold

Co-reporter:Paul A. Wender and Daryl Staveness

Organic Letters 2014 Volume 16(Issue 19) pp:5140-5143

Publication Date(Web):September 19, 2014

DOI:10.1021/ol502492b

Bryostatin 1, in clinical trials or preclinical development for cancer, Alzheimer’s disease, and a first-of-its-kind strategy for HIV/AIDS eradication, is neither readily available nor optimally suited for clinical use. In preceding work, we disclosed a new class of simplified bryostatin analogs designed for ease of access and tunable activity. Here we describe a final step diversification strategy that provides, in only 25 synthetic steps, simplified and tunable analogs with bryostatin-like PKC modulatory activities.

Computer-Guided Design, Synthesis, and Protein Kinase C Affinity of a New Salicylate-Based Class of Bryostatin Analogs

Co-reporter:Paul A. Wender, Yu Nakagawa, Katherine E. Near, and Daryl Staveness

Organic Letters 2014 Volume 16(Issue 19) pp:5136-5139

Publication Date(Web):September 19, 2014

DOI:10.1021/ol502491f

Bryostatin 1 is in clinical trials for the treatment of cancer and Alzheimer’s disease and is a candidate for a first-in-class approach to HIV/AIDS eradication. It is neither readily available nor optimally suited for clinical use. Using a function oriented synthesis strategy, a new class of bryostatin-inspired analogs was designed with a simplified salicylate-derived subunit, enabling step-economical synthesis (23 total steps) of agents exhibiting bryostatin-like affinity to protein kinase C (PKC).

Propargyltrimethylsilanes as Allene Equivalents in Transition Metal-Catalyzed [5 + 2] Cycloadditions

Co-reporter:Paul A. Wender, Fuyuhiko Inagaki, Magnus Pfaffenbach, and Matthew C. Stevens

Organic Letters 2014 Volume 16(Issue 11) pp:2923-2925

Publication Date(Web):May 12, 2014

DOI:10.1021/ol501114q

Conventional allenes have not been effective π-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.

Cell-Penetrating, Guanidinium-Rich Molecular Transporters for Overcoming Efflux-Mediated Multidrug Resistance

Co-reporter:Jessica R. Vargas, Erika Geihe Stanzl, Nelson N. H. Teng, and Paul A. Wender

Molecular Pharmaceutics 2014 Volume 11(Issue 8) pp:2553-2565

Publication Date(Web):May 5, 2014

DOI:10.1021/mp500161z

Fifteen Years of Cell-Penetrating, Guanidinium-Rich Molecular Transporters: Basic Science, Research Tools, and Clinical Applications

Co-reporter:Erika Geihe Stanzl, Brian M. Trantow, Jessica R. Vargas, and Paul A. Wender

Accounts of Chemical Research 2013 Volume 46(Issue 12) pp:2944

Publication Date(Web):May 22, 2013

DOI:10.1021/ar4000554

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.

Mechanistic and Computational Studies of Exocyclic Stereocontrol in the Synthesis of Bryostatin-like Cis-2,6-Disubstituted 4-Alkylidenetetrahydropyrans by Prins Cyclization

Co-reporter:Yasuyuki Ogawa, Phillip P. Painter, Dean J. Tantillo, and Paul A. Wender

The Journal of Organic Chemistry 2013 Volume 78(Issue 1) pp:104-115

Publication Date(Web):November 2, 2012

DOI:10.1021/jo301953h

The Prins cyclization of syn-β-hydroxy allylsilanes and aldehydes gives cis-2,6-disubstituted 4-alkylidenetetrahydropyrans as sole products in excellent yields regardless of the aldehyde (R″) or syn-β-hydroxy allylsilane substituent (R′) used. By reversing the R″ and R′ groups, complementary exocyclic stereocontrol can be achieved. When the anti-β-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.

Highly potent, synthetically accessible prostratin analogs induce latent HIV expression in vitro and ex vivo

Co-reporter:Elizabeth J. Beans;Dennis Fournogerakis;Carolyn Gauntlett;Lars V. Heumann;Rainer Kramer;Matthew D. Marsden;Danielle Murray;Tae-Wook Chun;Jerome A. Zack

PNAS 2013 Volume 110 (Issue 29 ) pp:11698-11703

Publication Date(Web):2013-07-16

DOI:10.1073/pnas.1302634110

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.

Ligand Effects on Rates and Regioselectivities of Rh(I)-Catalyzed (5 + 2) Cycloadditions: A Computational Study of Cyclooctadiene and Dinaphthocyclooctatetraene as Ligands

Co-reporter:Xiufang Xu ; Peng Liu ; Adam Lesser ; Lauren E. Sirois ; Paul A. Wender ;K. N. Houk

Journal of the American Chemical Society 2012 Volume 134(Issue 26) pp:11012-11025

Publication Date(Web):June 5, 2012

DOI:10.1021/ja3041724

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)]+SbF6– and [Rh(COD)]+SbF6–, which provide superior reactivities and regioselectivities relative to that of the previously reported [Rh(CO)2Cl]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 π/π and C–H/π 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)2Cl]2 catalyst to diminish the ligand–substrate repulsions or by using aryl alkynes, for which the ligand–substrate interactions become stabilizing due to π/π and C–H/π 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.

A molecular method for the delivery of small molecules and proteins across the cell wall of algae using molecular transporters

Co-reporter:Joel M. Hyman;Bahram Parvin;Erika I. Geihe;Brian M. Trantow

PNAS 2012 Volume 109 (Issue 33 ) pp:

Publication Date(Web):2012-08-14

DOI:10.1073/pnas.1202509109

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.

Designed guanidinium-rich amphipathic oligocarbonate molecular transporters complex, deliver and release siRNA in cells

Co-reporter:Erika I. Geihe;Christina B. Cooley;Matthew K. Kiesewetter;Jeff R. Simon;Justin A. Edward;Roger L. Kaspar;Robyn P. Hickerson;James L. Hedrick;Robert M. Waymouth

PNAS 2012 Volume 109 (Issue 33 ) pp:

Publication Date(Web):2012-08-14

DOI:10.1073/pnas.1211361109

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.

Rhodium Dinaphthocyclooctatetraene Complexes: Synthesis, Characterization and Catalytic Activity in [5+2] Cycloadditions

Co-reporter: Paul A. Wender;Adam B. Lesser ;Lauren E. Sirois

Angewandte Chemie International Edition 2012 Volume 51( Issue 11) pp:2736-2740

Publication Date(Web):

DOI:10.1002/anie.201108270

Rhodium Dinaphthocyclooctatetraene Complexes: Synthesis, Characterization and Catalytic Activity in [5+2] Cycloadditions

Co-reporter: Paul A. Wender;Adam B. Lesser ;Lauren E. Sirois

Angewandte Chemie 2012 Volume 124( Issue 11) pp:2790-2794

Publication Date(Web):

DOI:10.1002/ange.201108270

Total Synthesis of Bryostatin 9

Co-reporter:Paul A. Wender ;Adam J. Schrier

Journal of the American Chemical Society 2011 Volume 133(Issue 24) pp:9228-9231

Publication Date(Web):May 27, 2011

DOI:10.1021/ja203034k

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.

Translating Natures Library: The Bryostatins and Function-Oriented Synthesis

Co-reporter:Paul A. Wender;Brian A. Loy ;Adam J. Schrier

Israel Journal of Chemistry 2011 Volume 51( Issue 3-4) pp:453-472

Publication Date(Web):

DOI:10.1002/ijch.201100020

Abstract

We review in part our computational, design, synthesis, and biological studies on a remarkable class of compounds and their designed analogs that have led to preclinical candidates for the treatment of cancer, a first-in-class approach to Alzheimer’s disease, and a promising strategy to eradicate HIV/AIDS. Because these leads target, in part, protein kinase C (PKC) isozymes, they have therapeutic potential even beyond this striking set of therapeutic indications. This program has given rise to new synthetic methodology and represents an increasingly important direction of synthesis focused on achieving function through synthesis-informed design (function-oriented synthesis).

Design, synthesis, and evaluation of potent bryostatin analogs that modulate PKC translocation selectivity

Co-reporter:Paul A. Wender;Jeremy L. Baryza;Stacey E. Brenner;Brian A. DeChristopher;Brian A. Loy;Adam J. Schrier;Vishal A. Verma

PNAS 2011 108 (17 ) pp:6721-6726

Publication Date(Web):2011-04-26

DOI:10.1073/pnas.1015270108

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.

Editorial: To Eun Lee on His 65th Birthday

Co-reporter:Paul Wender

Chemistry – An Asian Journal 2011 Volume 6( Issue 8) pp:

Publication Date(Web):

DOI:10.1002/asia.201100574

No abstract is available for this article.

Design, synthesis, and evaluation of potent bryostatin analogs that modulate PKC translocation selectivity

Co-reporter:Paul A. Wender;Jeremy L. Baryza;Stacey E. Brenner;Brian A. DeChristopher;Brian A. Loy;Adam J. Schrier;Vishal A. Verma

PNAS 2011 108 (17 ) pp:6721-6726

Publication Date(Web):2011-04-26

DOI:10.1073/pnas.1015270108

Design, synthesis, and evaluation of potent bryostatin analogs that modulate PKC translocation selectivity

Co-reporter:Paul A. Wender;Jeremy L. Baryza;Stacey E. Brenner;Brian A. DeChristopher;Brian A. Loy;Adam J. Schrier;Vishal A. Verma

PNAS 2011 108 (17 ) pp:6721-6726

Publication Date(Web):2011-04-26

DOI:10.1073/pnas.1015270108

Function oriented synthesis: preparation and initial biological evaluation of new A-ring-modified bryologs

Co-reporter:Paul A. Wender, Jenny Reuber

Tetrahedron 2011 67(51) pp: 9998-10005

Publication Date(Web):

DOI:10.1016/j.tet.2011.09.058

A Metal-Catalyzed Intermolecular [5+2] Cycloaddition/Nazarov Cyclization Sequence and Cascade

Co-reporter:Paul A. Wender ; René T. Stemmler ;Lauren E. Sirois

Journal of the American Chemical Society 2010 Volume 132(Issue 8) pp:2532-2533

Publication Date(Web):February 8, 2010

DOI:10.1021/ja910696x

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.

Electronic and Steric Control of Regioselectivities in Rh(I)-Catalyzed (5 + 2) Cycloadditions: Experiment and Theory

Co-reporter:Peng Liu ; Lauren E. Sirois ; Paul Ha-Yeon Cheong ; Zhi-Xiang Yu ; Ingo V. Hartung ; Heiko Rieck ◻; Paul A. Wender ;K. N. Houk

Journal of the American Chemical Society 2010 Volume 132(Issue 29) pp:10127-10135

Publication Date(Web):June 30, 2010

DOI:10.1021/ja103253d

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.

Highly Efficient, Facile, Room Temperature Intermolecular [5 + 2] Cycloadditions Catalyzed by Cationic Rhodium(I): One Step to Cycloheptenes and Their Libraries

Co-reporter:Paul A. Wender, Lauren E. Sirois, René T. Stemmler and Travis J. Williams

Organic Letters 2010 Volume 12(Issue 7) pp:1604-1607

Publication Date(Web):March 2, 2010

DOI:10.1021/ol100337m

A cationic rhodium(I) complex―[(C10H8)Rh(cod)]+ SbF6−―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.

The Diene Effect: The Design, Development, and Mechanistic Investigation of Metal-Catalyzed Diene-yne, Diene-ene, and Diene-allene [2+2+1] Cycloaddition Reactions

Co-reporter:Mitchell P. Croatt

European Journal of Organic Chemistry 2010 Volume 2010( Issue 1) pp:19-32

Publication Date(Web):

DOI:10.1002/ejoc.200900929

Abstract

Metal-catalyzed diene-yne, diene-ene, and diene-allene [2+2+1] cycloaddition reactions provide new methods for the facile construction of highly functionalized five-membered rings. These reactions can be conducted with a variety of substrate substitution patterns and functional groups and often in the absence of solvent. The special reactivity of dienes, a key to enabling or enhancing the effectiveness of the [2+2+1] and other reactions, is significantly different from that of alkynes, alkenes, or allenes. For example, the [2+2+1] reaction of a diene-yne is accelerated compared to that of the corresponding ene-yne. An even more dramatic “diene effect” is found with diene-enes and diene-allenes. While bis-enes and ene-allenes are not reported to yield [2+2+1] cycloadducts, the related diene-enes and diene-allenes undergo efficient [2+2+1] cycloadditions, providing new routes to cyclopentanones and alkylidenecyclopentanones. Mechanistic studies suggest that the unique reactivity observed with dienes arises from their participation in the putative rate-determining reductive elimination step by providing an additional energy-lowering coordination site for the transition metal catalyst.

Oligocarbonate Molecular Transporters: Oligomerization-Based Syntheses and Cell-Penetrating Studies

Co-reporter:Christina B. Cooley ; Brian M. Trantow ; Fredrik Nederberg ; Matthew K. Kiesewetter ; James L. Hedrick ; Robert M. Waymouth

Journal of the American Chemical Society 2009 Volume 131(Issue 45) pp:16401-16403

Publication Date(Web):October 27, 2009

DOI:10.1021/ja907363k

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.

Cyclocarboamination of Alkynes with Aziridines: Synthesis of 2,3-Dihydropyrroles by a Catalyzed Formal [3 + 2] Cycloaddition

Co-reporter:Paul A. Wender ;Daniel Strand

Journal of the American Chemical Society 2009 Volume 131(Issue 22) pp:7528-7529

Publication Date(Web):May 12, 2009

DOI:10.1021/ja901799s

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.

Apoptolidins E and F, New Glycosylated Macrolactones Isolated from Nocardiopsis sp.

Co-reporter:Paul A. Wender and Kate E. Longcore

Organic Letters 2009 Volume 11(Issue 23) pp:5474-5477

Publication Date(Web):November 4, 2009

DOI:10.1021/ol902308v

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.

An Approach to the Site-Selective Diversification of Apoptolidin A with Peptide-Based Catalysts

Co-reporter:Chad A. Lewis, Kate E. Longcore, Scott J. Miller and Paul A. Wender

Journal of Natural Products 2009 Volume 72(Issue 10) pp:1864-1869

Publication Date(Web):September 21, 2009

DOI:10.1021/np9004932

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.

Rhodium(I)-Catalyzed [2+2], [2+2+2], and [2+2+2+2] Cycloadditions of Dienes or Alkynes with a Bis-ene

Co-reporter:Paul A. Wender, Mitchell P. Croatt and Björn Kühn

Organometallics 2009 Volume 28(Issue 20) pp:5841-5844

Publication Date(Web):September 30, 2009

DOI:10.1021/om9007373

A novel metal-catalyzed, all-alkene [2+2+2] cycloaddition reaction involving a strained and conformationally restricted bis-ene and a diene is reported.(1) Modification of the catalyst leads to competition with a diene-ene [2+2] reaction, and when an alkyne is used in place of the diene, [2+2+2] and [2+2+2+2] reactions occur involving the bis-ene and 1 or 2 equiv of the alkyne, respectively.

The Synthesis of Highly Substituted Cyclooctatetraene Scaffolds by Metal-Catalyzed [2+2+2+2] Cycloadditions: Studies on Regioselectivity, Dynamic Properties, and Metal Chelation

Co-reporter:PaulA. Wender ;JustinP. Christy;AdamB. Lesser ;MarcT. Gieseler

Angewandte Chemie International Edition 2009 Volume 48( Issue 41) pp:7687-7690

Publication Date(Web):

DOI:10.1002/anie.200903859

The Synthesis of Highly Substituted Cyclooctatetraene Scaffolds by Metal-Catalyzed [2+2+2+2] Cycloadditions: Studies on Regioselectivity, Dynamic Properties, and Metal Chelation

Co-reporter:PaulA. Wender ;JustinP. Christy;AdamB. Lesser ;MarcT. Gieseler

Angewandte Chemie 2009 Volume 121( Issue 41) pp:7823-7826

Publication Date(Web):

DOI:10.1002/ange.200903859

Function-Oriented Synthesis: Biological Evaluation of Laulimalide Analogues Derived from a Last Step Cross Metathesis Diversification Strategy

Co-reporter:Susan L. Mooberry, Michael K. Hilinski, Erin A. Clark and Paul A. Wender

Molecular Pharmaceutics 2008 Volume 5(Issue 5) pp:829-838

Publication Date(Web):July 29, 2008

DOI:10.1021/mp800043n

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 μM, 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 C23−C27 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.Keywords: antimitotics; Laulimalide; laulimalide analogues; metathesis; microtubule stabilizers; synthetic chemistry;

Overcoming multidrug resistance of small-molecule therapeutics through conjugation with releasable octaarginine transporters

Co-reporter:Thomas H. Pillow;Christopher H. Contag;Elena A. Dubikovskaya;Steve H. Thorne

PNAS 2008 Volume 105 (Issue 34 ) pp:12128-12133

Publication Date(Web):2008-08-26

DOI:10.1073/pnas.0805374105

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.

Practical Synthesis of Prostratin, DPP, and Their Analogs, Adjuvant Leads Against Latent HIV

Co-reporter:Paul A. Wender;Jung-Min Kee;Jeffrey M. Warrington

Science 2008 Volume 320(Issue 5876) pp:649-652

Publication Date(Web):02 May 2008

DOI:10.1126/science.1154690

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.

Real-time analysis of uptake and bioactivatable cleavage of luciferin-transporter conjugates in transgenic reporter mice

Co-reporter:Elena A. Goun;Lisa R. Jones;Jonathan B. Rothbard;Thomas H. Pillow;Rajesh Shinde;Christopher H. Contag

PNAS 2007 Volume 104 (Issue 25 ) pp:10340-10345

Publication Date(Web):2007-06-19

DOI:10.1073/pnas.0703919104

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.

Metal-Catalyzed [2+2+1] Cycloadditions of 1,3-Dienes, Allenes, and CO

Co-reporter:Paul A. Wender, Mitchell P. Croatt,Nicole M. Deschamps

Angewandte Chemie International Edition 2006 45(15) pp:2459-2462

Publication Date(Web):

DOI:10.1002/anie.200600300

Molecular Transporters: Synthesis of Oligoguanidinium Transporters and Their Application to Drug Delivery and Real-Time Imaging

Co-reporter:Elena A. Goun;Thomas H. Pillow;Lisa R. Jones;Jonathan B. Rothbard Dr. Dr.

ChemBioChem 2006 Volume 7(Issue 10) pp:

Publication Date(Web):14 SEP 2006

DOI:10.1002/cbic.200600171

Crossing borders. Methods to enhance or control selective passage of therapeutics or probes into or through biological barriers are a key to the future of drug therapy and many fundamental advances in science. One bioinspired strategy for crossing biological barriers is based on the use of molecular transporters, the focus of this minireview and our studies Stanford.

RhI-Catalyzed CC Bond Activation: Seven-Membered Ring Synthesis by a [6+1] Carbonylative Ring-Expansion Reaction of Allenylcyclobutanes

Co-reporter:Paul A. Wender ;Nicole M. Deschamps;Robert Sun

Angewandte Chemie International Edition 2006 Volume 45(Issue 24) pp:

Publication Date(Web):9 MAY 2006

DOI:10.1002/anie.200600806

Ever expanding: A Rh^I-catalyzed CC activation reaction of allenylcyclobutanes generates intermediate metallacycles that can be trapped with CO to produce a new [6+1] reaction. Functionalized monocyclic and bicyclic cycloheptenones are obtained in good-to-excellent yields with this [6+1] higher-order carbonylative cycloaddition reaction.

Metal-Catalyzed [2+2+1] Cycloadditions of 1,3-Dienes, Allenes, and CO

Co-reporter:Paul A. Wender ;Mitchell P. Croatt;Nicole M. Deschamps

Angewandte Chemie 2006 Volume 118(Issue 15) pp:

Publication Date(Web):9 MAR 2006

DOI:10.1002/ange.200600300

Der Kreis wird geschlossen: Die Rh^I-katalysierten Titelreaktionen verlaufen unter milden Bedingungen und mit guten bis ausgezeichneten Ausbeuten bei einer Katalysatorbeladung von nur 0.1 Mol-%. Die Dienylallene reagieren selektiv über die inneren Doppelbindungen der Allen- und Dieneinheiten, was eine Vielzahl an Substituenten ermöglicht. DCE=1,2-Dichlorethan, TFE=2,2,2-Trifluorethanol.

RhI-Catalyzed CC Bond Activation: Seven-Membered Ring Synthesis by a [6+1] Carbonylative Ring-Expansion Reaction of Allenylcyclobutanes

Co-reporter:Paul A. Wender ;Nicole M. Deschamps;Robert Sun

Angewandte Chemie 2006 Volume 118(Issue 24) pp:

Publication Date(Web):9 MAY 2006

DOI:10.1002/ange.200600806

Expandieren: Eine Rhodium(I)-katalysierte C-C-Aktivierung von Allenylcyclobutanen liefert Metallacyclen-Intermediate, die mit CO abgefangen werden. Funktionalisierte mono- wie bicyclische Cycloheptenone werden mit dieser neuen carbonylierenden [6+1]-Cycloaddition höherer Ordnung in guten bis ausgezeichneten Ausbeuten erhalten.

Simplified Analogs of Bryostatin with Anticancer Activity Display Greater Potency for Translocation of PKCδ-GFP

Co-reporter:Jeremy L. Baryza, Stacey E. Brenner, Madeleine L. Craske, Tobias Meyer, Paul A. Wender

Chemistry & Biology 2004 Volume 11(Issue 9) pp:1261-1267

Publication Date(Web):September 2004

DOI:10.1016/j.chembiol.2004.06.014

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 PKCδ-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.

Intermolecular Dienyl Pauson–Khand Reaction

Co-reporter:Paul A. Wender ;Nicole M. Deschamps;Travis J. Williams

Angewandte Chemie 2004 Volume 116(Issue 23) pp:

Publication Date(Web):13 MAY 2004

DOI:10.1002/ange.200454117

Drei-Komponenten-[2+2+1]-Cycloadditionen gelingen mit Dienen statt Alkenen in einer intermolekularen, Rh^I-katalysierten Variante der Pauson-Khand-Reaktion (siehe Schema). Die höhere Reaktivität der Diene ermöglicht einen effizienten Zugang zu Alkenylcyclopentenonen ausgehend von leicht erhältlichen Ausgangsstoffen. R¹, R²=Alkyl, Silyl, Carbonyl; R³=Me, Bn.

Intermolecular Dienyl Pauson–Khand Reaction

Co-reporter:Paul A. Wender ;Nicole M. Deschamps;Travis J. Williams

Angewandte Chemie International Edition 2004 Volume 43(Issue 23) pp:

Publication Date(Web):13 MAY 2004

DOI:10.1002/anie.200454117

Three-component [2+2+1] cycloadditions are facilitated by the use of dienes as activated two-carbon-atom components in a Rh^I-catalyzed intermolecular variant of the Pauson–Khand reaction (see scheme). The enhanced reactivity of the dienes allows efficient access to a variety of alkenyl cyclopentenones from commercially or readily available starting materials. R¹, R²=alkyl, silyl, carbonyl; R³=Me, Bn.

Microtubule-stabilizing agents based on designed laulimalide analogues

Co-reporter:Susan L. Mooberry;Deborah A. Randall-Hlubek;Sayee G. Hegde;Lei Zhang;Rachel M. Leal;Robert D. Hubbard

PNAS 2004 Volume 101 (Issue 23 ) pp:8803-8808

Publication Date(Web):2004-06-08

DOI:10.1073/pnas.0402759101

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 IC50 range of 0.12–16.5 μM. 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, C16-C17-des-epoxy laulimalide and C20-methoxy laulimalide, appear to have a mechanism of action identical to laulimalide. The C16-C17-des-epoxy, C20-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 C2-C3-alkynoate derivatives had lower potency, and they initiated abnormal microtubule structures but did not cause micronucleation or extensive G2/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.

The Dienyl Pauson–Khand Reaction

Co-reporter:Paul A. Wender ;Nicole M. Deschamps;Gabriel G. Gamber

Angewandte Chemie International Edition 2003 Volume 42(Issue 16) pp:

Publication Date(Web):23 APR 2003

DOI:10.1002/anie.200350949

The diene plays a key role in the Pauson–Khand [2+2+1] reaction of tethered dienynes (see scheme). These reactions are accelerated by the diene (relative to an alkene) and proceed in good to excellent yields, often at room temperature, in the presence of carbon monoxide, [RhCl(CO)(PPh₃)₂], and AgSbF₆.

The Dienyl Pauson–Khand Reaction

Co-reporter:Paul A. Wender ;Nicole M. Deschamps;Gabriel G. Gamber

Angewandte Chemie 2003 Volume 115(Issue 16) pp:

Publication Date(Web):23 APR 2003

DOI:10.1002/ange.200350949

Die Dien-Einheit spielt die Schlüsselrolle bei der Beschleunigung intramolekularer [2+2+1]-Pauson-Khand-Reaktionen von Dieninen (siehe Schema). In Gegenwart von Kohlenmonoxid, [RhCl(CO)(PPh₃)₂] und AgSbF₆ reagieren Dienine mit guten bis ausgezeichneten Ausbeuten und – im Unterschied zu vergleichbaren Eninen – oft bereits bei Raumtemperatur.

Beyond cell penetrating peptides: designed molecular transporters

Co-reporter:Paul A. Wender, Christina B. Cooley, Erika I. Geihe

Drug Discovery Today: Technologies (Spring 2012) Volume 9(Issue 1) pp:e49-e55

Publication Date(Web):1 March 2012

DOI:10.1016/j.ddtec.2011.07.004

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.

The design of guanidinium-rich transporters and their internalization mechanisms

Co-reporter:Paul A. Wender, Wesley C. Galliher, Elena A. Goun, Lisa R. Jones, Thomas H. Pillow

Advanced Drug Delivery Reviews (1 March 2008) Volume 60(Issues 4–5) pp:452-472

Publication Date(Web):1 March 2008

DOI:10.1016/j.addr.2007.10.016

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.

Function through bio-inspired, synthesis-informed design: step-economical syntheses of designed kinase inhibitors

Co-reporter:Paul A. Wender, Alison D. Axtman, Jennifer E. Golden, Jung-Min Kee, Lauren E. Sirois, Ryan V. Quiroz and Matthew C. Stevens

Inorganic Chemistry Frontiers 2014 - vol. 1(Issue 10) pp:NaN1171-1171

Publication Date(Web):2014/10/06

DOI:10.1039/C4QO00228H

The human kinome comprises over 500 protein kinases. When mutated or over-expressed, many play critical roles in abnormal cellular functions associated with cancer, cardiovascular disease and neurological disorders. Here we report a step-economical approach to designed kinase inhibitors inspired by the potent, but non-selective, natural product staurosporine, and synthetically enabled by a novel, complexity-increasing, serialized [5 + 2]/[4 + 2] cycloaddition strategy. This function-oriented synthesis approach rapidly affords tunable scaffolds, and produced a low nanomolar inhibitor of protein kinase C.