DESIGN, SYNTHESIS, AND BIOLOGICAL EVALUATION OF INDOLE-BASED VASCULAR DISRUPTING AGENTS FOR THE POTENTIAL TREATMENT OF CANCER
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An established strategy in therapeutic oncology entails selectively targeting the tubulin-microtubule system, resulting in inhibition or hyperstimulation of tubulin polymerization effecting cell cycle arrest at anaphase. More recently, it has been found that small molecule inhibitors of tubulin assembly, known as vascular disrupting agents (VDAs), damage tumor vasculature by inducing cell morphology changes in the endothelial cells lining tumor vasculature. Tumor vascular is poorly established compared to normal tissue vasculature, and is disproportionately susceptible to this form of disruption, allowing such compounds to be selective. A particular benchmark VDA isolated from the Combretum caffrum tree is the natural product combretastatin A-4 (CA4), which binds at the colchicine site located on the β subunit of the αβ tubulin heterodimer. Previous investigations in the Pinney Laboratory led to the discovery of an indole-based derivative of CA4 known as OXi8006 which demonstrates comparable inhibitory effects of tubulin polymerization and cancer cell growth to CA4. Herein, we report the design, synthesis, and biological evaluation of two new analogs of OXi8006 as potential VDAs for the treatment of cancer. Additionally, several advanced intermediates were prepared for future synthetic approaches to diversely functionalized analogs of OXi8006. Details of the chemical synthesis and collaborative biochemical evaluation are presented.