Design, synthesis and anti-tumor activity study of novel histone deacetylase inhibitors containing isatin-based caps and o-phenylenediamine-based zinc binding groups.

• 影响指数: 3.461
• 发表时间: 06 2017 15
• 来源期刊: Bioorg Med Chem
• DOI: 10.1016/j.bmc.2017.03.036
• PMID: 28511906
• 文章类型: Journal Article
• 中科院分区: Q3
• 方向: 医学
• 作者列表: Gao S,Zang J,Gao Q,Liang X,Ding Q,Li X,Xu W,Chou CJ,Zhang Y

关键词: Anticancer; Epigenetics; HDAC inhibitors; Isatin

Mesh: Cell Line, Tumor; Cell Proliferation / drug effects; Drug Design; Histone Deacetylase 1 / antagonists & inhibitors chemistry metabolism; Histone Deacetylase Inhibitors / chemical synthesis chemistry pharmacology; Humans; Isatin / analogs & derivatives chemical synthesis pharmacology; Molecular Docking Simulation; Neoplasms / drug therapy metabolism pathology; Phenylenediamines / chemical synthesis chemistry pharmacology; Zinc / metabolism

Abstract

As a hot topic of epigenetic studies, histone deacetylases (HDACs) are related to lots of diseases, especially cancer. Further researches indicated that different HDAC isoforms played various roles in a wide range of tumor types. Herein a novel series of HDAC inhibitors with isatin-based caps and o-phenylenediamine-based zinc binding groups have been designed and synthesized through scaffold hopping strategy. Among these compounds, the most potent compound 9n exhibited similar if not better HDAC inhibition and antiproliferative activities against multiple tumor cell lines compared with the positive control entinostat (MS-275). Additionally, compared with MS-275 (IC50 values for HDAC1, 2 and 3 were 0.163, 0.396 and 0.605µM, respectively), compound 9n with IC50 values of 0.032, 0.256 and 0.311µM for HDAC1, 2 and 3 respectively, showed a moderate HDAC1 selectivity.