The natural product paclitaxel (Taxol/R) is one of the most important currently available anticancer drugs. Its primary mechanism of action is to bind to polymerized tubulin and stabilize it, thus interfering with the mammalian cell cycle and triggering programmed cell death, or apoptosis. Three other natural products or groups of natural products, the epothilones, discodermolide, and eleutherobin and related compounds such as sarcodictyin, have all been found to act by essentially the same mechanism, even though they have very different chemical structures. The fundamental hypothesis of the proposed work is that the four compound classes mentioned above bind to tubulin in microtubules in similar but yet different ways, and that an understanding of the binding mode of each compound class will enable the design and synthesis of simplified compounds that bind as well as the natural products. The work proposed is divided into three related but distinct parts. . Modeling and synthesis of simplified analogs of paclitaxel, based on synthetic, biophysical, rotational-echo double-resonance/REDOR NMR, and modeling studies that point to one particular structure as the constrained paclitaxel conformer that best mimics paclitaxel's tubulin-bound conformation. . Modeling, synthetic, biophysical, and REDOR NMR studies of the epothilones, discodermolide, and eleutherobin that will lead to a rigorous definition of the tubulin-binding conformations and modes of these compounds. . Synthesis of constrained analogs of the epothilones, discodermolide, and eleutherobin that mimic the binding conformations elucidated in the second part. The ultimate goal of the work is to design, synthesize, and evaluate simplified analogs of paclitaxel, the epothilones, discodermolide, and eleutherobin, which will bind effectively to polymerized tubulin. Such compounds are expected to show good tubulin polymerization and cytotoxic properties, and may thus become synthetically accessible anticancer agents.
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