Microtubules are dynamic
polymers that occur in eukaryotic cells and play important roles in cell division, motility, transport and signaling. They form during the process of polymerization of α- and β-
tubulin dimers.
Tubulin is a significant and heavily researched molecular target for anticancer drugs. Combretastatins are natural cis-
stilbenes that exhibit cytotoxic properties in cultured
cancer cells in vitro.
Combretastatin A-4 (3'-hydroxy-3,4,4',5-tetramethoxy-cis-
stilbene; CA-4) is a potent cytotoxic cis-
stilbene that binds to β-
tubulin at the
colchicine-binding site and inhibits
tubulin polymerization. The
prodrug CA-4
phosphate is currently in clinical trials as a chemotherapeutic agent for
cancer treatment. Numerous series of
stilbene analogs have been studied in search of potent
cytotoxic agents with the requisite
tubulin-interactive properties. Microtubule-interfering agents include numerous CA-4 and transresveratrol analogs and other synthetic
stilbene derivatives. Importantly, these agents are active in both
tumor cells and immature endothelial cells of
tumor blood vessels, where they inhibit the process of angiogenesis. Recently, computer-aided virtual screening was used to select potent
tubulin-interactive compounds. This review covers the role of
stilbene derivatives as a class of
antitumor agents that act by targeting microtubule assembly dynamics. Additionally, we present the results of molecular modeling of their binding to specific sites on the α- and β-
tubulin heterodimer. This has enabled the elucidation of the mechanism of
stilbene cytotoxicity and is useful in the design of novel agents with improved anti-mitotic activity.
Tubulin-interactive agents are believed to have the potential to play a significant role in the fight against
cancer.