Structural Modifications of OXi8006 Leading to New Indole-Based Anti-Cancer Agents

Abstract

A promising method for treating cancer involves selectively targeting the tumor vascular network. Tumor vascular is characterized as a disorganized and convoluted network of microvessels, in contrast to normal tissue vasculature, presenting an ideal target for small molecule intervention. Small-molecule anti-cancer agents, known as vascular disrupting agents (VDAs), function by damaging existing tumor vasculature through an essential binding interaction at the dynamic tubulin-protein system effecting vessel occlusion and collapse. This selective binding ultimately deprives tumors of vital nutrients and oxygen necessary for growth resulting in hypoxia and tumor necrosis. A particular benchmark VDA isolated from the bark of the South African bush willow tree Combretum caffrum is combretastatin A-4 (CA4). This compound demonstrates exceptional inhibition of tubulin assembly. Previous investigations in the Pinney Lab led to the development of an indole-based VDA modeled after CA4 known as OXi8006. OXi8006 exhibits inhibition of tubulin polymerization comparable to CA4 and demonstrates strong cytotoxicity against human cancer cell lines. In an effort to better understand the biochemical mechanisms of action and fully evaluate the biological activity of OXi8006 sufficient amounts of the compound are necessary. In addition to the resynthesis of OXi8006, structural modifications on the indole scaffold will provide insight into the biological activity and tubulin assembly inhibition with respect to regioselective functionalizations. In addition, modified analogues of OXi8006 can lead to the discovery of new potent VDAs. Herein, we report the total synthesis and biological evaluation of OXi8006 and a diphenolic derivative. Furthermore, the preparation of advanced intermediates en route to future diversely functionalized analogues is presented.