Development of hydroxamate-based histone deacetylase inhibitors containing 1,2,4-oxadiazole moiety core with antitumor activities

Bioorg Med Chem Lett. 2019 Jan 1;29(1):15-21. doi: 10.1016/j.bmcl.2018.11.027.

Feifei Yang ¹, Peipei Shan ², Na Zhao ¹, Di Ge ¹, Kongkai Zhu ¹, Cheng-Shi Jiang ¹, Peifeng Li ³, Hua Zhang ⁴

Affiliations

1 School of Biological Science and Technology, University of Jinan, Jinan, Shandong Province 250022, China.
2 Institute for Translation Medicine, Qingdao University, Qingdao, Shandong Province 266071, China.
3 Institute for Translation Medicine, Qingdao University, Qingdao, Shandong Province 266071, China. Electronic address: peifli@hotmail.com.
4 School of Biological Science and Technology, University of Jinan, Jinan, Shandong Province 250022, China. Electronic address: bio_zhangh@ujn.edu.cn.

PMID: 30455152 DOI: 10.1016/j.bmcl.2018.11.027

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, compounds 11a and 11c increased acetylation of histone H3 and H4 in dose-dependent manner. Furthermore, 11a and 11c remarkably induced Apoptosis in HepG2 Cancer cells. Finally, the high potency of compound 11a was rationalized by molecular docking studies.

Keywords

1,2,4-Oxadiazole; Antitumor; HDAC inhibitors; Hydroxamate; Structure-activity relationships.

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