1. Synthesis and biological evaluation of aminobenzamides containing purine moiety as class I histone deacetylases inhibitors.
- Author
-
Mao PT, He WB, Mai X, Feng LH, Li N, Liao YJ, Zhu CS, Li J, Chen T, Liu SH, Zhang QM, and He L
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Benzamides chemical synthesis, Benzamides chemistry, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Histone Deacetylase Inhibitors chemical synthesis, Histone Deacetylase Inhibitors chemistry, Humans, Molecular Docking Simulation, Molecular Structure, Purines chemistry, Structure-Activity Relationship, Antineoplastic Agents pharmacology, Benzamides pharmacology, Histone Deacetylase Inhibitors pharmacology, Histone Deacetylases metabolism, Purines pharmacology
- 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., (Copyright © 2021. Published by Elsevier Ltd.)
- Published
- 2022
- Full Text
- View/download PDF