Design and Synthesis of Vascular Disrupting Agents that Bear the Indole Molecular Framework
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The discovery of colchicine and combretastatin A-4 (CA4), two naturally occurring compounds that inhibit tubulin polymerization, have spurred great interest in small-molecule anticancer agents that interact with the tubulin-microtubule protein system and function as antiproliferative agents. A subset of these analogues target established vasculature feeding tumors and are referred to as vascular disrupting agents (VDAs). It has been discovered that a variety of molecules bearing the indole molecular framework that mimic structural features of colchicine and CA4 function as potent inhibitors of tubulin polymerization and demonstrate promise as VDAs. The Pinney Research Group (Baylor University) previously designed and synthesized OXi8006, an indole-bearing VDA that functions as a powerful inhibitor of tubulin polymerization and demonstrates strong cytotoxicity against a variety of human cancer cell lines. Inspired by these previous studies, a variety of OXi8006 analogues have been prepared by chemical synthesis and evaluated in preliminary biological studies (carried out through collaboration).