The Solid State, Solution and Tubulin-Bound Conformations of Agents that Promote Microtubule Stabilization
James P. Snyder.
Taxol (paclitaxel), a complex diterpene obtained from Taxus brevifolia and its semisynthetic analogue Taxotere are two of the most important new drugs for cancer chemotherapy. Their mechanism of cytotoxic action involves stabilization of microtubules leading to mitotic arrest. A similar mechanism has been proposed for an expanding set of other natural products, for instance, the epothilones, eleutherobin, the sarcodictyins, discodermolide, laulimalide, Rhazinilam, WS9885B, certain steroids and a group of polyisoprenyl benzophenones. In this review, we focus on the conformations of small molecule microtubule (MT) stabilizing compounds which have been isolated or synthesized and subjected to structural analysis. NMR and fluorescense spectroscopies, X-ray crystallography, high resolution microscopy (electron crystallography) and theoretical calculations comprise the most common methods used in this context. In particular, we describe how the structures were determined and with what accuracy. We also discuss the conformational diversity apparent from the three dimensional structures and compare the various proposals for bioactive conformations at the target MT binding sites. Of critical importance are the recently disclosed models for Taxol and its biomimetics binding to β-tubulin. Several different conformational schemes derived from both pharmacophore construction and modeled protein ligand complexes are compared and critically evaluated. Although full consensus has yet to be reached, emphasis is placed on pharmacophore models for the various anti-MT agents that are internally consistent and encompass more than one structural class.
Keywords: Tubulin Bound Conformations, Microtubule Stabilization, Taxol paclitaxel, Taxus brevifolia, Taxotere, Epothilones, Eleutherobin, Sarcodictyins, Discodermolide, Laulimalide
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