Synthesis and antitumor activity of aza-brazilan derivatives containing imidazolium salt pharmacophore
The synthesis of a series of novel aza-brazilan derivatives containing imidazolium salt pharmacophores is presented. Biological activity of such imidazolium salts was further evaluated in vitro against a panel of human tumor cell lines. The results suggest that the electron-withdrawing group on the aza-brazilan moiety, substituted 5,6-dimethyl-benzimidazoless ring and substitution of the imidazolyl-3-position with a 4-methylbenzyl group were essential for modulating cytotoxic activity. Compounds 55 and 39, bearing a 4-methylbenzyl substituent at position-3 of 5,6-dimethyl-benzimidazole, were found to be the most potent compounds with IC50 values of 0.52-1.30 μM and 0.56-1.51 μM against four human tumor cell lines investigated. Particularly, compound 57 exhibited inhibitory activity against MCF-7 cell line with IC50 value of 0.35 μM and 56-fold more sensitive to DDP. Moreover, compound 55 inhibited cell proliferation through inducing the G0/G1 cell cycle arrest and apoptosis in SMMC-7721 cells.