Design, synthesis and biological activity of 4-(4-benzyloxy)phenoxypiperidines as selective and reversible LSD1 inhibitors

Jiayue Xi; Siyuan Xu; Lulu Zhang; Xueyuan Bi; Yanshen Ren; Yu-Chih Liu; Yueqing Gu; Yungen Xu; Fei Lan; Xiaoming Zha

doi:10.1016/j.bioorg.2018.02.016

Design, synthesis and biological activity of 4-(4-benzyloxy)phenoxypiperidines as selective and reversible LSD1 inhibitors

Bioorg Chem. 2018 Aug:78:7-16. doi: 10.1016/j.bioorg.2018.02.016. Epub 2018 Feb 16.

Authors

Jiayue Xi¹, Siyuan Xu², Lulu Zhang³, Xueyuan Bi⁴, Yanshen Ren⁴, Yu-Chih Liu⁵, Yueqing Gu⁴, Yungen Xu⁶, Fei Lan⁷, Xiaoming Zha⁸

Affiliations

¹ Department of Pharmaceutical Engineering & Department of Biochemical Engineering, 639 Longmian Avenue, Nanjing 211198, PR China; Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
² Laboratory of Epigenetics, Institute of Biochemical Sciences, Fudan University, 131 Dong'An Road, Shanghai 200032, PR China.
³ Department of Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, PR China.
⁴ Department of Pharmaceutical Engineering & Department of Biochemical Engineering, 639 Longmian Avenue, Nanjing 211198, PR China.
⁵ Shanghai ChemPartner Co., Ltd., Zhangjiang Hi-Tech Park, Shanghai 201203, PR China.
⁶ Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
⁷ Laboratory of Epigenetics, Institute of Biochemical Sciences, Fudan University, 131 Dong'An Road, Shanghai 200032, PR China. Electronic address: fei_lan@fudan.edu.cn.
⁸ Department of Pharmaceutical Engineering & Department of Biochemical Engineering, 639 Longmian Avenue, Nanjing 211198, PR China. Electronic address: xmzha@cpu.edu.cn.

PMID: 29524666
DOI: 10.1016/j.bioorg.2018.02.016

Abstract

Lysine specific demethylase 1 (LSD1) plays a vital role in epigenetic regulation of gene activation and repression in several human cancers and is recognized as a promising antitumor therapeutic target. In this paper, a series of 4-(4-benzyloxy)phenoxypiperidines were synthesized and evaluated. Among the tested compounds, compound 10d exhibited the potent and reversible inhibitory activity against LSD1 in vitro (IC₅₀ = 4 μM). Molecular docking was conducted to predict its binding mode. Furthermore, 10d displayed it could inhibit migration of HCT-116 colon cancer cells and A549 lung cancer cells. Taken together, 10d deserves further investigation as a hit-to-lead for the treatment of LSD1 associated tumors.

Keywords: Inhibitors; LSD1; Migration; Reversible; Selective.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Histone Demethylases / antagonists & inhibitors*
Histone Demethylases / metabolism
Humans
Molecular Docking Simulation
Molecular Structure
Piperidines / chemical synthesis
Piperidines / chemistry
Piperidines / pharmacology*
Structure-Activity Relationship
Tumor Cells, Cultured
Wound Healing / drug effects

Substances

Antineoplastic Agents
Enzyme Inhibitors
Piperidines
Histone Demethylases
KDM1A protein, human