Chemistry of Tubulin-Interactive Anticancer Agents - Kingston Group

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Chemistry of Tubulin-Interactive Anticancer Agents

As noted above, the complex diterpenoid taxol is an exciting anti-cancer drug that is currently in clinical use against ovarian and breast cancer. It acts by an unusual mechanism of promoting microtubule assembly, and we are studying this by the synthesis of specifically labeled analogs, with the aim of identifying the nature of the binding of taxol to microtubules. Based on this information, we have developed a model of the tubulin-binding shape of taxol, and have prepared a cyclic constrained analog of taxol that is more active than the parent compound, thus validating our model. We are now preparing simplified analogs based on this preferred shape, with the expectation that one or more of these will lead to readily accessible active anticancer agents. This project thus blends synthesis, biological studies, and molecular modeling in an integrated effort to improve on one of the most important new anti-cancer natural products of the past 30 years.

In addition to taxol, we have begun to study three additional natural products: epothilone B, discodermolide, and eleutherobin. These compounds are all in clinical trials or in clinical development as anticancer agents, and they all act by the same basic mechanism of action as taxol. They are very different structurally, however, and thus we are studying exactly how they bind to tubulin and whether we can prepare simplified active analogs.

Selected Publications

Y. Li, B. Poliks, L. Cegelski, M. Poliks, Z. Gryczynski, G. Piszczek, P. G. Jagtap, D. R. Studelska, D. G. I. Kingston, J. Schaefer, and S. Bane, "The Conformation of Microtubule-Bound Paclitaxel Determined by Fluorescence Spectroscopy and REDOR NMR." Biochemistry, 2000, 39, 281-291.

Y. Li, R. Edsall, Jr., P. G. Jagtap, D. G. I Kingston, and S. Bane "Equilibrium Studies of a Fluorescent Paclitaxel Derivative Binding to Microtubules." Biochemistry, 2000, 39, 616-623.

D. G. I. Kingston. Recent Advances in the Chemistry of Taxol. J. Nat. Prod, 2000, 63, 726-734.

L. He, P. G. Jagtap, D. G. I. Kingston, H.-J. Shen, G. A. Orr, and S. B.Horwitz. A Common Pharmacophore for Taxol and the Epothilones Based on the Biological Activity of a Taxane Molecule Lacking a C-13 Side Chain. Biochemistry, 2000, 39, 3972-3978.

H. Yuan and D. G. I. Kingston "Synthesis and Biological Evaluation of C-6 and C-7 Modified Paclitaxels." Tetrahedron, 2000, 56, 6407-6414.

M. D. Chordia, H. Yuan, P. G. Jagtap, J. F. Kadow, B. H. Long, C. R. Fairchild, K. A. Johnston, and D. G. I. Kingston "Synthesis and Bioactivity of 2,4-Diacyl Analogs of Paclitaxel." Bioorg. Med. Chem. 2001, 9, 171-178.

D. G. I. Kingston "Taxol, a Molecule for All Seasons." Chem. Comm. 2001, 867-880.

E. Baloglu, D. G. I. Kingston, P. Patel, S. K. Chatterjee, and S. Bane "Synthesis and Microtubule Binding of Fluorescent Paclitaxel Derivatives." Bioorg. Med. Chem. Lett. 2001, 11, 2249-2252.

B. B. Metaferia, J. Hoch, T. E. Glass, S. L. Bane, S. K. Chatterjee, J. P. Snyder, A. Lakdawala, B. Cornett, and D. G. I. Kingston, "Synthesis and Biological Evaluation of Novel Macrocyclic Paclitaxel Analogs." Org. Lett. 2001, 3, 2461-2464.

P. G. Jagtap, E. Baloglu, D. M. Barron, S. Bane, and D. G. I. Kingston, "Design and Synthesis of a Combinatorial Chemistry Library of 10-Acyl and 7,10-Diacyl Analogues of Paclitaxel (Taxol"!) Using Solid Phase Synthesis" J. Nat. Prod. 2002, 65, 1136-1142.

C. Liu, M. Tamm, M. W. Nötzel, A. de Meijere, J. K. Schilling, and D. G. I. Kingston "Synthesis, structure, and bioactivities of paclitaxel analogs with a cyclopropanated side-chain." Tetrahedron Lett. 2003, 44, 2049-2052.

E. Baloglu, J. M. Hoch, D. M. Barron, S. Bane, and D. G. I. Kingston "Synthesis and Biological Evaluation of C-3'NH/C-10 and C-2/C-10 Modified Paclitaxel Analogs" Bioorg. Med. Chem. 2003, 11, 1557-1568.

D. G. I. Kingston, "What Makes Epothilones Stick?" Chem. & Biol. 2004, 11, 153-155.

C. Liu, J. S. Strobl, S. Bane, J. K. Schilling, M. McCracken, S. K. Chatterjee, R. Rahim-Bata, and D. G. I. Kingston. "Design, Synthesis and Bioactivities of Steroid Linked Taxol Analogs as Potential Targeted Drugs for Prostate and Breast Cancer." J. Nat. Prod. 2004, 67, 152-159.

T. Ganesh, R. C. Guza, S. Bane,ð ðR. Ravindra, N. Shanker, A. S. Lakdawala, J. P. Snyder, and D. G. I. Kingston, "The Bioactive Taxol Conformation on bð-tubulin: Experimental Evidence from Highly Active Constrained Analogs." Proc. Natl. Acad. Sci USA, 2004, 101, 10006-10011.

C. Liu, J. K. Schilling, R. Ravindra, S. L.Bane, and D. G. I. Kingston, "Syntheses and bioactivities of macrocyclic paclitaxel bis-lactones." Bioorg. Med. Chem. 2004, 12, in press.

C. Liu, M. Tamm, M. W. Nötzel, A. de Meijere, J. K. Schilling, A. Lakdawala, J. P. Snyder, S. L. Bane, N. Shanker, R. Ravindra, and D. G. I. Kingston, "C3' Cyclopropanated Taxol Analogs: Synthesis, Bioassay and Biostructural Analysis." J. Org. Chem., submitted.

D. G. I. Kingston. "Recent Advances in the Chemistry of Taxol in 2000 Years of Natural Products Research: Past, Present and Future" edited by Teus Luijendijk, Phytoconsult, Leiden, The Netherlands, 2000, pp. 81-104.

D. G. I. Kingston, H. Yuan, P. J. Jagtap, and L. Samala, "The Chemistry of Taxol and Related Taxoids" in "Progress in the Chemistry of Organic Natural Products, Volume 84" edited by W. Herz, H. Falk, and G. W. Kirby, Springer-Verlag, Wien; 2002, pp. 53-225.

D. J. Newman, G. M. Cragg, and D. G. I. Kingston, "Natural Products as Pharmaceuticals and Sources for Lead Structures" in The Practice of Medicinal Chemistry, 2nd Edition, edited by C. G. Wermuth, Academic Press, London, 2003 (published May 2003).