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

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.
Taotao Feng 1,  Dongdong Li 1,  Hai Wang 1,  Jian Zhuang 2,  Fang Liu 1,  Qichao Bao 1,  Yonghua Lei 1,  Weilin Chen 1,  Xiaojin Zhang 3,  Xiaoli Xu 4,  Haopeng Sun 4,  Qidong You 5,  Xiaoke Guo 6
Affiliations

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.

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