A series of
combretastatin A-4 (CA-4) analogues have been prepared from (Z)-substituted diarylacrylonitriles (1a-1p) obtained in a two-step synthesis from appropriate arylaldehydes and acrylonitriles. The resulting 4,5-disubstituted 2H-1,2,3-triazoles were evaluated for their anti-
cancer activities against a panel of 60 human
cancer cell lines. The diarylacrylonitrile analogue 2l exhibited the most potent anti-
cancer activity in the screening studies, with GI₅₀ values of <10 nM against almost all the cell lines in the human
cancer cell panel and TGI values of <10 nM against
cancer cell lines SF-539, MDA-MB-435, OVCAR-3 and A498. Furthermore, in silico docking studies of compounds 2l, 2e and 2h within the active site of
tubulin were carried out in order to rationalize the mechanism of the anti-
cancer properties of these compounds. From the in silico studies, compound 2e was predicted to have better affinity for the
colchicine binding site on
tubulin compared to compounds 2l and 2h. Analogue 2e was also evaluated for its anti-
cancer activity by colony formation assay against 9LSF rat
gliosarcoma cells and afforded an LD₅₀ of 7.5 nM. A cell cycle redistribution assay using analogue 2e was conducted to further understand the mechanism of action of these CA-4 analogues. From this study, analogues 2e and 2l were the most potent anti-
cancer agents in this structural class, and were considered lead compounds for further development as anti-
cancer drugs.