Synthesis and antitumor activity of aza-brazilan derivatives containing imidazolium salt pharmacophores

Abstract

The synthesis of a series of novel aza-brazilan derivatives containing imidazolium salt pharmacophores is presented. The biological activity of such imidazolium salts was further evaluated <i>in vitro</i> 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-benzimidazole ring and substitution of the imidazolyl-3-position with a 4-methylbenzyl group were essential for modulating the cytotoxic activity. Compounds <b>55</b> and <b>39</b>, 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 <b>57</b> exhibited inhibitory activity against the MCF-7 cell line with an IC₅₀ value of 0.35 μM and was 56-fold more sensitive than DDP. Moreover, compound <b>55</b> inhibited cell proliferation through inducing G0/G1 cell cycle arrest and apoptosis in SMMC-7721 cells.