Synthesis and biological evaluation of novel (E)-N'-(2,3-dihydro-1H-inden-1-ylidene) benzohydrazides as potent LSD1 inhibitors

Yang Zhou; Yan Li; Wen-Jing Wang; Pu Xiang; Xin-Mei Luo; Li Yang; Sheng-Yong Yang; Ying-Lan Zhao

doi:10.1016/j.bmcl.2015.06.054

Synthesis and biological evaluation of novel (E)-N'-(2,3-dihydro-1H-inden-1-ylidene) benzohydrazides as potent LSD1 inhibitors

Bioorg Med Chem Lett. 2016 Sep 15;26(18):4552-4557. doi: 10.1016/j.bmcl.2015.06.054. Epub 2015 Jun 20.

Authors

Yang Zhou¹, Yan Li¹, Wen-Jing Wang¹, Pu Xiang¹, Xin-Mei Luo¹, Li Yang¹, Sheng-Yong Yang¹, Ying-Lan Zhao²

Affiliations

¹ State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medicinal School, Sichuan University, Chengdu 610041, Sichuan, China.
² State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medicinal School, Sichuan University, Chengdu 610041, Sichuan, China. Electronic address: zhaoyinglan@scu.edu.cn.

PMID: 27524309
DOI: 10.1016/j.bmcl.2015.06.054

Abstract

Lysine specific demethylase 1 (LSD1) plays an important role in regulating histone lysine methylation at residues K4 and K9 on histone H3 and is recognized as an attractive therapeutic target in multiple malignancies. In this study, a series of novel (E)-N'-(2,3-dihydro-1H-inden-1-ylidene) benzohydrazides were synthesized and biologically evaluated for their potential LSD1 inhibitory effect. Among them, compounds 5a and 5n showed the most potent LSD1 inhibitory activity with IC50 values of 1.4 and 1.7nM, respectively, which were about 10 times more potent compared with (E)-N-(1-(5-chloro-2-hydroxyphenyl) ethylidene)-3-(morpholinosulf-only) benzohydrazide (J. Med. Chem.2013, 56, 9496-9508; as reference compound). Compounds 5a and 5n also exhibited marked anti-proliferation activities against cancer cell lines that highly expressed LSD1. These results suggest that these optimized compounds might be served as promising LSD1 inhibitors against cancer, which merit further study.

Keywords: Anticancer; Conformational constraint; Histone methyltransferase; Lysine specific demethylase 1 (LSD1).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Histone Demethylases / antagonists & inhibitors*
Hydrogen Bonding
Molecular Conformation
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Histone Demethylases
KDM1A protein, human