Microtubule-binding agents (MBAs) which destabilize microtubules and promote depolymerization interfere with the mitotic spindle assembly during cell division resulting in cell death. This is the main reason for utilizing such molecules as anti-cancer agents. A natural product, combretastatin A-4 (CA-4), isolated from the bark of the South African tree Combretum caffrum is a well-established microtubule binding agent. From structure-activity relationship (SAR) studies, the cis-orientation of the trimethoxyphenyl ring system on the double bond of the CA-4 molecule is essential for the cytotoxic effects of this compound. However, even though CA-4 is a potent microtubule binding agent, it possesses disadvantages such as vascular disruption, low solubility, and isomerization to the less active trans-isomer (trans-CA-4) in solution. Four novel series of combretastatin A-4 analogs have been designed and several compounds have been synthesized in each series. These series include benzothiophene acrylonitrile analogs, heterocyclic (2H)-1,2,3-triazoles analogs, aromatic and heteroaromatic analogs, and tetrazole analogs.
Several compounds from each series exhibited potent cytotoxic activity against various human cancer cell lines. Select compounds were evaluated in a tubulin polymerization assay and were found to inhibit tubulin polymerization.