Design, synthesis and biological evaluation of novel 2-aminobenzamides containing dithiocarbamate moiety as histone deacetylase inhibitors and potent antitumor agents.

A novel series of 2-aminobenzamides with dithiocarbamate as cap group were designed and synthesized as histone deacetylase (HDAC) inhibitors. Most newly synthesized compounds displayed potent antiproliferative activity against diverse human tumor cell lines. The most potent compounds, M101, M122 and M133 exhibited remarkably enhanced anticancer potency against 6 kinds of cancer cell lines with IC50 values of as low as 0.54-2.49 μM compared with CS055 (2.28∼ >26 μM) and MS275 (0.47-6.74 μM). HDAC isoform selectivity assay indicated that M101, M122 and M133 are HDAC1 and HDAC2 selective inhibitors. We also rationalize the high potency and selectivity of compound M122 by molecular docking. Further investigation showed that M101, M122 and M133 could inhibit colony formation of human hepatocellular carcinoma cell line SMMC7721. Furthermore, M101, M122 and M133 remarkably induced apoptosis in SMMC7721 cancer cells. M101 and M133 were found to potently induce SMMC7721 cancer cell cycle arrest at G2/M phase. This study demonstrated that introducing dithiocarbamate as the capping group of 2-aminobenzamide is effective for improving both HDAC inhibitory activity and antitumor activity. The most potent compounds, M101, M122 and M133 could be promising candidates for cancer therapy.