Development of hydroxamate-based histone deacetylase inhibitors containing 1, 2, 4-oxadiazole moiety core with antitumor activities. Issue 1 (1st January 2019)

• Record Type: Journal Article
• Authors: Yang, Feifei; Shan, Peipei; Zhao, Na; Ge, Di; Zhu, Kongkai; Jiang, Cheng-shi; Li, Peifeng; Zhang, Hua
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 1(2019)
• Page Start: 15
• Page End: 21
• Publication Date: 2019-01-01
• Subjects: 1, 2, 4-Oxadiazole -- Hydroxamate -- HDAC inhibitors -- Structure-activity relationships -- Antitumor; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.11.027
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: Thirteen new hydroxamate-based bis-substituted aromatic amide HDAC inhibitors with 1, 2, 4-oxadiazole core were obtained. The structures were elucidated by comprehensive spectroscopic analyses. Three compounds displayed excellent HDAC1 inhibitory effects and significant anti-proliferative activities. Two compounds increased acetylation of histone H3 and H4 in dose-dependent manner. Two compounds remarkably induced apoptosis in HepG2 cancer cells. Abstract: Histone deacetylases (HDACs) has proved to be promising target for the development of antitumor drugs. In this study, we reported the design and synthesis of a class of novel hydroxamate-based bis-substituted aromatic amide HDAC inhibitors with 1, 2, 4-oxadiazole core. Most newly synthesized compounds displayed excellent HDAC1 inhibitory effects and significant anti-proliferative activities. Among them, compounds11a and11c increased acetylation of histone H3 and H4 in dose-dependent manner. Furthermore, 11a and11c remarkably induced apoptosis in HepG2 cancer cells. Finally, the high potency of compound11a was rationalized by molecular docking studies.