Tubulin is an important protein in cells wherein it self-assembles to form microtubules (MTs) which play an important role as cytoskeletal elements and as transport mechanisms for cellular organelles. Small molecule interactions with tubulin have been and continue to be among the most important techniques for study of the dynamics and control mechanisms of MT formation. In addition, these small molecule ligands of tubulin have proven to be of considerable medical significance. Colchicine is the best known of these ligands and has many medical applications from gout to biliary cirrhosis. Taxol, a more recently discovered tubulin ligand, is currently in Phase II clinical trials as an anticancer agent. Taxol and colchicine both interfere with MT function but do so by different mechanisms. Colchicine and its analogs interfere with MT-dependent processes by binding to tubulin and inhibiting polymerization of tubulin into MTs. Taxol, in contrast, binds to tubulin in assembled MTs as they form and stabilizes abnormal and non- functional MTs. In this project, judiciously designed biaryl analogs of colchicine with strategically placed functional groups with potential for irreversible binding will be prepared to serve as markers of the colchicine binding site. To explore the interaction of taxol with MTs, simple esters of the isoserine moiety of the taxol molecule will be prepared and examined for MT binding activity. The isoserine portion of the taxol molecule has been shown to be essential for taxol's activity. Although this project is designed to elucidate the molecular and biochemical mechanisms of these to major antitubulin drugs, any new compounds developed during this research may find potential application in any of a number of MT-related disorders.
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