Synthesis and biological evaluation of aminobenzamides containing purine moiety as class I histone deacetylases inhibitors
| Autor: | Ping-Ting Mao, Wei-Bao He, Xi Mai, Li-Hua Feng, Na Li, Yi-Jing Liao, Cai-Sheng Zhu, Jian Li, Ting Chen, Shu-Hao Liu, Qi-Ming Zhang, Ling He |
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| Rok vydání: | 2021 |
| Předmět: |
Dose-Response Relationship
Drug Molecular Structure Cell Survival Organic Chemistry Clinical Biochemistry Pharmaceutical Science Antineoplastic Agents Biochemistry Histone Deacetylases Histone Deacetylase Inhibitors Molecular Docking Simulation Structure-Activity Relationship Purines Cell Line Tumor Drug Discovery Benzamides Molecular Medicine Humans Drug Screening Assays Antitumor Molecular Biology Cell Proliferation |
| Zdroj: | Bioorganicmedicinal chemistry. 56 |
| ISSN: | 1464-3391 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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