Discovery of tranylcypromine analogs with an acylhydrazone substituent as LSD1 inactivators: Design, synthesis and their biological evaluation

Kai Sun; Jia-Di Peng; Feng-Zhi Suo; Ting Zhang; Yun-Dong Fu; Yi-Chao Zheng; Hong-Min Liu

doi:10.1016/j.bmcl.2017.10.003

Discovery of tranylcypromine analogs with an acylhydrazone substituent as LSD1 inactivators: Design, synthesis and their biological evaluation

Bioorg Med Chem Lett. 2017 Nov 15;27(22):5036-5039. doi: 10.1016/j.bmcl.2017.10.003. Epub 2017 Oct 3.

Authors

Kai Sun¹, Jia-Di Peng¹, Feng-Zhi Suo¹, Ting Zhang¹, Yun-Dong Fu¹, Yi-Chao Zheng², Hong-Min Liu³

Affiliations

¹ Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, PR China; Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, PR China; Key Laboratory of Henan Province for Drug Quality and Evaluation, PR China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China.
² Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, PR China; Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, PR China; Key Laboratory of Henan Province for Drug Quality and Evaluation, PR China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China; National Center for International Research of Micro-nano Molding Technology & Key Laboratory for Micro Molding Technology of Henan Province, Zhengzhou University, Zhengzhou 450001, PR China. Electronic address: yichaozheng@zzu.edu.cn.
³ Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, PR China; Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, PR China; Key Laboratory of Henan Province for Drug Quality and Evaluation, PR China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China. Electronic address: liuhm@zzu.edu.cn.

PMID: 29037950
DOI: 10.1016/j.bmcl.2017.10.003

Abstract

Lysine specific demethylase 1 (LSD1), the first identified histone demethylase, plays an important role in epigenetic regulation of gene activation and repression, has been reported to be up-regulated and involved in numbers of solid malignant tumors. In this study, we identified a series of phenylalanyl hydrazones based LSD1 inhibitors, and the most potent one, compound 4q, can inactivate LSD1 with IC₅₀ = 91.83 nM. In cellular level, compound 4q can induce the accumulation of CD86 as well as H3K4me2, and inhibit gastric cancer cell proliferation by inactivating LSD1. Our findings indicated that compound 4q may serve as a potential leading compound to target LSD1 overexpressed gastric cancer.

Keywords: Inhibitor; LSD1; Phenylalanyl hydrazones; Tranylcypromine.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / toxicity
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects
Epithelial-Mesenchymal Transition / drug effects
Histone Demethylases / antagonists & inhibitors
Histone Demethylases / metabolism*
Humans
Hydrazones / chemistry*
Inhibitory Concentration 50
Structure-Activity Relationship
Tranylcypromine / analogs & derivatives*
Tranylcypromine / chemical synthesis
Tranylcypromine / toxicity

Substances

Antineoplastic Agents
Hydrazones
Tranylcypromine
Histone Demethylases
KDM1A protein, human