Synthesis and biological evaluation of aminobenzamides containing purine moiety as class I histone deacetylases inhibitors

  • Bioorg Med Chem. 2022 Feb 15;56:116599. doi: 10.1016/j.bmc.2021.116599.
Ping-Ting Mao  1 ,  Wei-Bao He  1 ,  Xi Mai  2 ,  Li-Hua Feng  1 ,  Na Li  1 ,  Yi-Jing Liao  1 ,  Cai-Sheng Zhu  1 ,  Jian Li  1 ,  Ting Chen  1 ,  Shu-Hao Liu  1 ,  Qi-Ming Zhang  1 ,  Ling He  1
Affiliations
  • 1. School of Pharmaceutical Sciences, Nanchang University, Nanchang 330006, China.
  • 2. School of Pharmaceutical Sciences, Nanchang University, Nanchang 330006, China. Electronic address: [email protected].
PMID: 35041998 DOI: 10.1016/j.bmc.2021.116599
Abstract

The aminobenzamide is selective to class I histone deacetylases (HDACs) and displays unique tight-binding/slow-off HDAC-binding mechanism. Herein, we report a series of 9-substituted purine aminobenzamides that selectively inhibit class I HDACs. The activities in vitro showed compound 9d exhibited 12 folds more potent than MS-275 against HDAC1 isoform and showed excellent inhibitory activity on Cancer cells, including HCT-116, MDA-MB-231, K562 cell lines. The metabolic stability of 9d was much better than that of the well-known HDAC Inhibitor SAHA. Pulse exposure test of western blot assay demonstrated that 9a, 9d induced histone acetylation in a similar manner to MS-275. Further biological validation demonstrated that 9d prevented cell transition from G1 phase to S phase by reducing Cyclin D1, CDK2 and lifting p21, induced early Apoptosis by upregulating Bax and downregulating Bcl-2 in HCT-116 cells.

Keywords
Aminobenzamide; Antiproliferative; Histone deacetylase inhibitors; Metabolic stability; Purine.
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