个人简介

Education Ph.D University of Illinois 1990 B.S. University of Illinois 1985 B.A. Ohio Wesleyan University 1984 NIH Postdoctoral Fellow, University of South Carolina 1990-1993 Professional Experience Professor of Chemistry Baylor University 1993-

研究领域

Organic Chemistry

A primary focus of the research efforts of my group lies in the total synthesis of structurally challenging and biologically relevant and interesting natural products. Specifically, we have a special interest in the synthesis of anti-tumor, anti-mitotic agents (such as rhizoxin) which mediate their biological activity through an interaction with tubulin. The development of a unified synthetic approach to compounds of this type accomplishes several goals: 1) It provides the opportunity to evaluate small portions of the total molecule (available only through synthesis) for their biochemical activity with tubulin. 2) It affords new insight into chemical transformations and serves to "test" and expand the tools of asymmetric synthesis. 3) A concise synthetic route to a natural product provides a means to modify the existing structure thereby preparing derivatives which may, in fact, be more biologically active than their "parent" natural product. 4) Total synthesis, in and of itself, often displays itself as a monumental accomplishment which reflects the history, versatility, collective knowledge, reasoning, and artistic accruement of the overall discipline of organic chemistry. Molecular Probes for Tubulin An important goal in the evaluation of potential chemotherapeutic agents continues to center on the establishment of mechanisms of action by which these compounds exert their biological effects. A detailed understanding of a particular biological mode of action is important not only for the efficient design of new, more potent drugs, but also to glean additional insight into the etiology of the given disease itself. A variety of clinically-promising compounds which demonstrate potent cytotoxic and antitumor activity are known to effect their primary mode of action through an efficient inhibition of tubulin polymerization. This class of compounds undergoes an initial binding interaction to the protein tubulin which in turn arrests the ability of tubulin to polymerize into microtubules which are essential components for cell maintenance and division. The development of both photosensitive and chemical (electrophilic) molecular probes for tubulin is therefore of significance in order to learn detailed information concerning the "chemical environment" of the "small molecule" binding domain of tubulin. Information of this nature is paramount for the design of new more potent inhibitors of tubulin polymerization and hence improved, more effective antitumor agents. Radiochemical Synthesis The ultimate success of a particular molecular probe is often synergistically linked to our ability to prepare the probe in radiolabeled form for detailed biochemical evaluation. We maintain an active interest in establishing new, facile, and general synthetic transformations which allow the incorporation of tritium and other radioisotopes in high specific activity into a given molecular framework. Molecular Modeling We have an active and ongoing interest in learning as much as possible concerning small molecule-large molecule interactions such as those involved in a ligand binding to an enzyme or protein. Molecular modeling, including energy minimization, conformational analysis, docking characteristics, and molecular dynamics is an extremely useful technique for the systematic, theoretical evaluation of complex interactions of this nature. It is our intention that information gained from molecular modeling studies will suggest new ligands for synthesis and add to the overall collective knowledge of binding interactions.

近期论文

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Mechanistic considerations in the synthesis of 2-aryl-indole analogues under Bischler–Mohlau conditions. MacDonough, M. T.; Shi, Z.; Pinney, K. G. Tetrahedron Letters, in press, 2015. Synthesis of Structurally Diverse Benzosuberene Analogues and their Biological Evaluation as Anti-cancer Agents. Tanpure, R. P.; George, C. S.; Strecker, T. E.; Devkota, L.; Tidmore, J. K.; Lin, C.-M.; Herdman, C. A.; MacDonough, M. T.; Sriram, M.; Chaplin, D. J.; Trawick, M. L.; Pinney, K. G. Bioorganic and Medicinal Chemistry, 21, 8019-8032, 2013. Synthesis of 2-Aryl-3-Aroyl-Indole Salt (OXi8007) Resembling Combretastatin A-4 with Application as a Vascular Disrupting Agent. Hadimani, M. B.; MacDonough, M. T.; Ghatak, A.; Strecker, T. E.; Lopez, R.; Sriram, M.; Nguyen, B. L.; Hall, J. J.; Kessler, R. J.; Shirali, A. R.; Liu, L.; Garner, C. M.; Pettit, G. R.; Hamel, E.; Chaplin, D. J.; Mason, R. P.; Trawick, M. L.; Pinney, K. G. Journal of Natural Products, 76, 1668-1678, 2013. Synthesis and Biological Evaluation of Indole-based, Anti-cancer Agents Inspired by the Vascular Disrupting Agent 2-(3′-hydroxy-4′-methoxyphenyl)-3-(3″,4″,5″-trimethoxybenzoyl)-6-methoxyindole (OXi8006). MacDonough, M. T.; Strecker, T. E.; Hamel, E.; Hall, J. J.; Chaplin, D. J.; Trawick, M. L.; Pinney, K. G.Bioorganic and Medicinal Chemistry, 21, 6831-6843, 2013. Small-Molecule Inhibitors of Cathepsin L Incorporating Functionalized Ring-Fused Molecular Frameworks. Song, J.; Jones, L. M.; Chavarria, G. E.; Charlton-Sevcik, A. K.; Jantz, A.; Johansen, A.; Bayeh, L.; Soeung, V.; Snyder, L. K.; Lade, Jr., S. D.; Chaplin, D. J.; Trawick, M. L.; Pinney, K. G. Bioorganic Medicinal Chemistry Letters, 23: 2801-2807, 2013. Initial Evaluation of the Antitumour Activity of KGP94, a Functionalized Benzophenone Thiosemicarbazone Inhibitor of Cathepsin L. Chavarria, G. E.; Horsman, M. R.; Arispe, W. M.; Kumar, G. D. K.; Chen, S.-E.; Strecker, T. E.; Parker, E. N.; Chaplin, D. J.; Pinney, K. G.; Trawick, M. L. European Journal of Medicinal Chemistry, 58: 568-572,2012. Synthesis and Biochemical Evaluation of Thiochromanone Thiosemicarbazone Analogues as Inhibitors of Cathepsin L. Song, J.; Jones, L. M.; Kumar, G. D. K.; Conner, E. S.; Bayeh, L.; Chavarria, G. E.; Charlton-Sevcik, A. K.; Chen, S.-E.; Chaplin, D. J.; Trawick, M. L.; Pinney, K. G. ACS Medicinal Chemistry Letters, 3: 450-453,2012. An Amino-Benzosuberene Analogue That Inhibits Tubulin Assembly and Demonstrates Remarkable Cytotoxicity. *Tanpure, R. P.; *George, C. S.; *Sriram, M.; Strecker, T. E.; Tidmore, J. K.; Hamel, E.; Charlton-Sevcik, A. K.; Chaplin, D. J.; Trawick, M. L.; Pinney, K. G. MedChemComm, 3: 720-724, 2012. [* denotes authors with equal contributions] Regioselective Synthesis of Water Soluble Monophosphate Derivatives of Combretastatin A-1. Tanpure, R. P.; Nguyen, B. L.; Strecker, T. E.; Aguirre, S.; Sharma, S.; Chaplin, D. J.; Siim, B. G.; Hamel, E.; Lippert, J. W. III; Pettit, G. R.; Trawick, M. L.; Pinney, K. G. Journal of Natural Products 74: 1568-1574,2011. A Perspective on Vascular Disrupting Agents that Interact with Tubulin: Preclinical Tumor Imaging and Biological Assessment. Mason, R. P.; Zhao, D.; Liu, L.; Trawick, M. L.; Pinney, K. G. Integr. Biol. 3: 375-387, 2011. (Invited contribution to honor Professor Mina J. Bissell for her lifetime contributions to the tumor microenvironment and research involving the extracellular matrix) Functionalized Benzophenone, Thiophene, Pyridine, and Fluorene Thiosemicarbazone Derivatives as Inhibitors of Cathepsin L . Kumar, G. D. K.; Chavarria, G. E.; Charlton-Sevcik, A. K.; Yoo, G. K.; Song, J.; Strecker, T. E.; Siim, B. G.; Chaplin, D. J.; Trawick, M. L.; Pinney, K. G. Bioorg. Med. Chem. Lett. 20: 6610-6615, 2010. Regio- and Stereospecific Synthesis of Mono ß-D-Glucuronic Acid Derivatives of Combretastatin A-1. Tanpure, R. P.; Strecker, T. E.; Chaplin, D. J.; Siim, B. G.; Trawick, M. L.; Pinney, K. G. J. Nat. Prod. 73: 1093-1101, 2010. Design, synthesis, and biological evaluation of potent thiosemicarbazone based cathepsin L inhibitors. Kumar, G. D. K.; Chavarria, G. E.; Charlton-Sevcik, A. K.; Arispe, W. M.; MacDonough, M. T.; Strecker, T. E.; Chen, S.-E.; Siim, B. G.; Chaplin, D. J.; Trawick, M. L.; Pinney, K. G. Bioorg. Med. Chem. Lett. 20: 1415-1419, 2010. Application of the McMurry Coupling Reaction in the Synthesis of Tri- and Tetra-arylethylene Analogues as Potential Cancer Chemotherapeutic Agents. Tanpure, R. P.; Harkrider, A. R.; Strecker, T. E.; Hamel, E.; Trawick, M. L.; Pinney, K. G. Bioorg. Med. Chem. 17: 6993-7001, 2009. Carbon-14 Radiosynthesis of Combretastatin A-1 (CA1) and its Corresponding Phosphate Prodrug (CA1P). Brown, R. T.; Murrell, V. L.; McMordie, A.; Sriram, M.; Pinney, K. G.; Sharma, S.; Chaplin, D. J. J. Labelled Compd. Rad., 52: 567-570, 2009. Development of Synthetic Methodology Suitable for the Radiosynthesis of Combretastatin A-1 (CA1) and its Corresponding Prodrug CA1P. Shirali, A.; Sriram, M.; Hall, J. J.; Nguyen, B. L.; Guddneppanavar, R.; Hadimani, M. B.; Ackley, J. F.; Siles, R.; Jelinek, C. J.; Arthasery, P.; Brown, R. C.; Murrell, V. L.; McMordie, A.; Sharma, S.; Chaplin, D. J.; Pinney, K. G. J. Nat. Prod. 72: 414-421, 2009. Design, Synthesis and Biological Evaluation of Dihydronaphthalene and Benzosuberene Analogs of the Combretastatins as Inhibitors of Tubulin Polymerization in Cancer Chemotherapy. Sriram, M.; Hall, J. J.; Grohmann, N. C.; Strecker, T. E.; Wootton, T.; Franken, A.; Trawick, M. L.; Pinney, K. G. Bioorg. Med. Chem. 16: 8161-8171, 2008. Design, Synthesis, Biochemical, and Biological Evaluation of Nitrogen-Containing Triflouro Structural Modifications of Combretastatin A-4. Hall, J. J.; Sriram, M.; Strecker, T. E.; Tidmore, J. K.; Jelinek, C. J.; Kumar, G. D. K.; Hadimani, M. B.; Pettit, G. R.; Chaplin, D. J.; Trawick, M. L.; Pinney, K. G. Bioorg. Med. Chem. Lett. 18: 5146-5149, 2008.