Targeting Hypoxia with Small-Molecule Anticancer Agents

Abstract

A vascular network delivers nutrients and oxygen to solid tumors, therefore selectively targeting tumor vasculature with anticancer agents represents a potentially promising therapeutic strategy. Small-molecule anticancer compounds that interact at the colchicine-binding site on beta-tubulin and inhibit microtubule formation can function as cytotoxic agents. In addition, a sub-set of these inhibitors of tubulin polymerization selectively disrupt blood flow to tumors and are referred to as vascular disrupting agents (VDAs). Through their ability to inhibit tubulin polymerization, VDAs induce morphology changes in the endothelial cells lining tumor vasculature, leading to vessel damage and ultimately precluding blood flow to the tumor. A variety of solid tumor cancers contain pronounced regions of low oxygen (hypoxia). In order to selectively target tumor hypoxia, small-molecule tubulin-binding agents (both antiproliferative agents and VDAs) can be synthetically linked to bioreductive triggers such as monomethyl or dimethyl nitrothiophenes, forming bioreductively activatable prodrug conjugates (BAPCs) that are designed to selectively release the anticancer agent in regions of hypoxia. The natural product combretastatin A-1 (CA1) and a synthetic analogue, phenstatin, are potent inhibitors of tubulin polymerization (IC50 = 1.9 μM and 1.0 μM, respectively) and CA1 functions as a VDA. The focus of this study centers on the synthesis of CA1 BAPCs that incorporate a monomethyl trigger and a phenstatin BAPC bearing a dimethyl trigger.