Novel 5-carboxy-8-HQ based histone demethylase JMJD2A inhibitors: introduction of an additional carboxyl group at the C-2 position of quinoline

Taotao Feng; Dongdong Li; Hai Wang; Jian Zhuang; Fang Liu; Qichao Bao; Yonghua Lei; Weilin Chen; Xiaojin Zhang; Xiaoli Xu; Haopeng Sun; Qidong You; Xiaoke Guo

doi:10.1016/j.ejmech.2015.09.013

Novel 5-carboxy-8-HQ based histone demethylase JMJD2A inhibitors: introduction of an additional carboxyl group at the C-2 position of quinoline

Eur J Med Chem. 2015 Nov 13:105:145-55. doi: 10.1016/j.ejmech.2015.09.013. Epub 2015 Sep 10.

Authors

Taotao Feng¹, Dongdong Li¹, Hai Wang¹, Jian Zhuang², Fang Liu¹, Qichao Bao¹, Yonghua Lei¹, Weilin Chen¹, Xiaojin Zhang³, Xiaoli Xu⁴, Haopeng Sun⁴, Qidong You⁵, Xiaoke Guo⁶

Affiliations

¹ State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
² Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
³ State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Organic Chemistry, School of Science, China Pharmaceutical University, Nanjing 210009, China.
⁴ State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
⁵ State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: youqidong@gmail.com.
⁶ State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: kexin95@126.com.

PMID: 26491978
DOI: 10.1016/j.ejmech.2015.09.013

Abstract

A series of JMJD2A inhibitors had been designed by analyzing the binding mode of 5-carboxy-8-hydroxyquinoline (5-carboxy-8-HQ) with JMJD2A. The inhibitory activity of the synthesized compounds against JMJD2A was determined, followed by docking simulations to understand the structure-activity relationships. Compounds with potent JMJD2A inhibitory activity demonstrated outstanding selectivity for JMJD2A over PHD2. Several potent compounds were selected to evaluate their anti-proliferative activity on tumor cell lines. Among them, compound 6p displayed the best anti-proliferative activity. Based on these in vitro biological data, seven compounds were chosen to determine their physicochemical properties. Compound 6p displayed good aqueous solubility and better permeability than 5-carboxy-8-HQ. Our data recognized that compound 6p could be considered as a starting point for development of new JmjC inhibitors.

Keywords: 5-Carboxy-8-hydroxyquinoline; Anti-tumor; JMJD2A inhibitors; Physicochemical properties.

Publication types

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

MeSH terms

Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology*
HCT116 Cells
Humans
Hydroxyquinolines / chemical synthesis
Hydroxyquinolines / chemistry
Hydroxyquinolines / pharmacology*
Jumonji Domain-Containing Histone Demethylases / antagonists & inhibitors*
Jumonji Domain-Containing Histone Demethylases / metabolism
MCF-7 Cells
Molecular Dynamics Simulation
Molecular Structure
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Hydroxyquinolines
Jumonji Domain-Containing Histone Demethylases
KDM4A protein, human
5-carboxy-8-hydroxyquinoline