Development of hydroxamate-based histone deacetylase inhibitors of bis-substituted aromatic amides with antitumor activities

Abstract

Previously, we designed and synthesized a series of bis-substituted aromatic amide-based histone deacetylase (HDAC) inhibitors. In this study, we report the replacement of a bromine atom by different amides on the phenyl ring of the CAP region. Representative compounds 9d and 10k exhibited low nanomolar IC₅₀ values against HDAC1, which were ten times lower than that of the positive control SAHA. The IC₅₀ of 9d against the human A549 cancer cell line was 2.13 μM. Furthermore, 9d increased the acetylation of histones H3 and H4 in a dose-dependent manner. Moreover, 9d significantly arrested A549 cells at the G2/M phase and induced A549 cell apoptosis. Finally, molecular docking investigation rationalized the high potency of compound 9d.