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

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

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

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 eactivity relationships. Compounds with potent JMJD2A inhibitory activity demonstrated outstanding selectivity for JMJD2A over PHD2. Several potent compounds were selected to evaluate their antiproliferative activity on tumor cell lines. Among them, compound 6p displayed the best antiproliferative 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.

Original language	English (US)
Pages (from-to)	145-155
Number of pages	11
Journal	European journal of medicinal chemistry
Volume	105
DOIs	https://doi.org/10.1016/j.ejmech.2015.09.013
State	Published - Nov 13 2015
Externally published	Yes

Keywords

5-Carboxy-8-hydroxyquinoline
Anti-tumor
JMJD2A inhibitors
Physicochemical properties

ASJC Scopus subject areas

Pharmacology
Drug Discovery
Organic Chemistry

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10.1016/j.ejmech.2015.09.013

Cite this

Feng, T., Li, D., Wang, H., Zhuang, J., Liu, F., Bao, Q., Lei, Y., Chen, W., Zhang, X., Xu, X., Sun, H., You, Q., & Guo, X. (2015). Novel 5-carboxy-8-HQ based histone demethylase JMJD2A inhibitors: Introduction of an additional carboxyl group at the C-2 position of quinoline. European journal of medicinal chemistry, 105, 145-155. https://doi.org/10.1016/j.ejmech.2015.09.013

Feng, T, Li, D, Wang, H, Zhuang, J, Liu, F, Bao, Q, Lei, Y, Chen, W, Zhang, X, Xu, X, Sun, H, You, Q & Guo, X 2015, 'Novel 5-carboxy-8-HQ based histone demethylase JMJD2A inhibitors: Introduction of an additional carboxyl group at the C-2 position of quinoline', European journal of medicinal chemistry, vol. 105, pp. 145-155. https://doi.org/10.1016/j.ejmech.2015.09.013

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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 eactivity relationships. Compounds with potent JMJD2A inhibitory activity demonstrated outstanding selectivity for JMJD2A over PHD2. Several potent compounds were selected to evaluate their antiproliferative activity on tumor cell lines. Among them, compound 6p displayed the best antiproliferative 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",

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

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doi = "10.1016/j.ejmech.2015.09.013",

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T2 - Introduction of an additional carboxyl group at the C-2 position of quinoline

AU - Feng, Taotao

AU - Li, Dongdong

AU - Wang, Hai

AU - Zhuang, Jian

AU - Liu, Fang

AU - Bao, Qichao

AU - Lei, Yonghua

AU - Chen, Weilin

AU - Zhang, Xiaojin

AU - Xu, Xiaoli

AU - Sun, Haopeng

AU - You, Qidong

AU - Guo, Xiaoke

PY - 2015/11/13

Y1 - 2015/11/13

N2 - 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 eactivity relationships. Compounds with potent JMJD2A inhibitory activity demonstrated outstanding selectivity for JMJD2A over PHD2. Several potent compounds were selected to evaluate their antiproliferative activity on tumor cell lines. Among them, compound 6p displayed the best antiproliferative 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.

AB - 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 eactivity relationships. Compounds with potent JMJD2A inhibitory activity demonstrated outstanding selectivity for JMJD2A over PHD2. Several potent compounds were selected to evaluate their antiproliferative activity on tumor cell lines. Among them, compound 6p displayed the best antiproliferative 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.

KW - 5-Carboxy-8-hydroxyquinoline

KW - Anti-tumor

KW - JMJD2A inhibitors

KW - Physicochemical properties

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ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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