Synthesis and antitumor activity of novel steroidal imidazolium salt derivatives

Sixty-one novel steroidal imidazolium salt derivatives were synthesized and evaluated in vitro against a panel of human tumor cell lines. The results showed that diosgenin‒imidazolium salt derivatives displayed much higher cytotoxic activities than cholesterol‒imidazolium salts and dehydroepiandrosterone‒imidazolium salts. The SARs results suggested that the existence of substituted 5,6-dimethyl-benzimidazoles or benzimidazole ring and substitution of the imidazolyl-3α-position with a 2-bromobenzyl or 2-naphthylmethyl group could be critical for promoting cytotoxic activity. Diosgenin‒imidazolium salt a30 was found to be the most potent compound with IC50 values of 0.44–0.79 μM against five human tumor cell lines. Compound a24 showed inhibitory activity selectively against SMMC-7721 cell lines with IC50 value of 0.21 μM and 54-fold more sensitive to DDP. Moreover, compound a30 inhibited cell proliferation through inducing the G0/G1 cell cycle arrest and apoptosis in SMMC-7721 cells. [Display omitted] •A series of sixty-one novel steroidal imidazolium salt derivatives were prepared.•Compound a30 was found to be the most potent compound with antitumor activity.•Compound a24 showed inhibitory activity selectively against SMMC-7721 cells.•The structure-activity relationship results of imidazolium salts were summarized.•Compound a30 induced the G0/G1 phase cell cycle arrest and apoptosis in SMMC-7721.