Development of combretastatins as potent tubulin polymerization inhibitors

The combretastatins are isolated from South African tree combretum caffrum kuntze. The lead compound combretastatin A-4 has displayed remarkable cytotoxic effect in a wide variety of preclinical tumor models and inhibits tubulin polymerization by interacting at colchicine binding site of microtubule. However, the structural simplicity of C A-4 is favorable for synthesis of various derivatives projected to induce rapid and selective vascular shutdown in tumors. Majority of the molecules have shown excellent antiproliferative activity and are able to inhibit tubulin polymerization as well as possible mechanisms of action have been investigated. In this review article, the synthesis and structure-activity relationships of C A-4 and immense number of its synthetic derivatives with various modifications on the A, B-rings, bridge carbons and their anti mitotic activities are discussed.