Design, synthesis and biological evaluation of novel hydroxamates and 2-aminobenzamides as potent histone deacetylase inhibitors and antitumor agents

Abstract

Many studies have indicated that histone deacetylase (HDAC) inhibitors are promising agents for the treatment of cancer. With the aim to search for novel potent HDAC inhibitors, we designed and synthesized two series of hydroxamates and 2-aminobenzamides compounds as HDAC inhibitors and antitumor agents. Those compounds were investigated for their HDAC enzymatic inhibitory activities and in vitro anti-proliferation activities against diverse cancer cell line (A549, HepG2, MGC80-3 and HCT116). Most of the synthesized compounds displayed potent HDAC inhibitory activity and antiproliferative activity. In particular, Compound 12a, N-(2-aminophenyl)-4-[(4-fluorophenoxy)methyl]benzamide, was shown to have the most HDAC inhibitory activity (70.6% inhibition at 5 μM) and antitumor activity with IC50 value of as low as 3.84 μM against HepG2 human liver hepatocellular carcinoma cell line, more than 4.8-fold lower than CS055 and 5.9-fold lower than CI994. HDAC isoform selectivity assay indicated 12a is a potent HDAC2 inhibitor. Docking study of 12a suggested that it bound tightly to the binding pocket of HDAC2. Further investigation showed that 12a could inhibit the migration and colony formation of A549 cancer cells. Furthermore, 12a remarkably induced apoptosis and G2/M phase cell cycle arrest in A549 cancer cells. Those results indicated that compound 12a could be a promising candidate for treatment of cancer.

Keywords: 2-Aminobenzamides; Antiproliferation; Histone deacetylase inhibitor; Hydroxamates; Molecular docking.