The naturally occurring diterpenoid taxol is a potent anticancer agent which shows activity in several operates by a unique mechanism of action in which it binds to the polymerized form of the cellular protein tubulin and promotes the assembly of microtubules. It does so in such a way, however, that the microtubule organizing centers are disrupted and also so that the assembled microtubules are dysfunctional, leading to an overall antimitotic effect. Taxol currently suffers from supply problems, however, since it is only available by isolation from the bark of the western yew, Taxus brevifolia. The long-term objective of the proposed work is to increase understanding of the taxol-polymerized tubulin interaction so that improved taxol derivatives can be designed and prepared by synthesis.
the specific aims are to determine the nature of the binding site on polymerized tubulin for taxol. Taxol derivatives will be prepared with photoreactive groups attached, and the labeled taxol will be irradiated in the presence of tubulin to yield covalently modified tubulin. Partial digestion of the tubulin, isolation of the modified peptides, and sequencing by MS/MS techniques will yield information on the nature of the taxol binding site on tubulin from other sources, will lead to a deeper understanding of the nature of tubulin polymerization and of the requirements for the taxol binding site, and may thus lead to the development of improved taxol analogs as anticancer drugs.
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