Design, synthesis and biological evaluation of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates containing sulfonamido as potential PI3Kα inhibitors

Yong Yin; Jia-Qin Hu; Xu Wu; Shao Sha; She-Feng Wang; Fang Qiao; Zhong-Cheng Song; Hai-Liang Zhu

doi:10.1016/j.bmc.2019.04.021

Design, synthesis and biological evaluation of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates containing sulfonamido as potential PI3Kα inhibitors

Bioorg Med Chem. 2019 Jun 1;27(11):2261-2267. doi: 10.1016/j.bmc.2019.04.021. Epub 2019 Apr 15.

Authors

Yong Yin¹, Jia-Qin Hu², Xu Wu³, Shao Sha³, She-Feng Wang³, Fang Qiao³, Zhong-Cheng Song⁴, Hai-Liang Zhu⁵

Affiliations

¹ Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.
² State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China; The Joint Research Centre of Gene Interference, Guangzhou University and Keele University for Gene Interference and Application, School of Life Science, Guangzhou University, 230 Waihuan West Road, Guangzhou 510006, People's Republic of China.
³ State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.
⁴ School of Chemistry & Environmental Engineering, Jiangsu University of Technology, 1801 Zhongwu Rd., Changzhou, Jiangsu 213001, People's Republic of China. Electronic address: songzhongcheng@jsut.edu.cn.
⁵ State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China. Electronic address: zhuhl@nju.edu.cn.

PMID: 31029551
DOI: 10.1016/j.bmc.2019.04.021

Abstract

A series of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates contained sulfonamido were designed and synthesized, and their anticancer effects in vitro was evaluated to develop some new PI3Kα inhibitors. Most of desired compounds exhibited the better antiproliferative activities against four cancer cell lines than that of LY294002. Out of them, compound 4o displayed the potent antiproliferative activity and high selectivity against the PI3Kα protein and it can induce apoptosis of HCT116 in a dose-dependent manner. Western blot assay indicated that compound 4o obviously down-regulated expression of p-Akt (S473). Molecular docking was performed to clarify the possible binding mode between compound 4o and PI3Kα. All these results indicated that compound 4o could be a potential inhibitor of PI3Kα.

Keywords: Anticancer; Chromeno[4,3-c]pyrazol-4(2H)-one derivates; Molecular docking; PI3Kα.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology
Apoptosis / drug effects
Catalytic Domain
Cell Line, Tumor
Cell Proliferation / drug effects
Coumarins / chemical synthesis
Coumarins / metabolism
Coumarins / pharmacology*
Drug Design
Drug Screening Assays, Antitumor
Humans
Molecular Docking Simulation
Phosphatidylinositol 3-Kinases / chemistry
Phosphatidylinositol 3-Kinases / metabolism*
Phosphoinositide-3 Kinase Inhibitors / chemical synthesis
Phosphoinositide-3 Kinase Inhibitors / metabolism
Phosphoinositide-3 Kinase Inhibitors / pharmacology*
Protein Binding
Pyrazoles / chemical synthesis
Pyrazoles / metabolism
Pyrazoles / pharmacology*
Sulfonamides / chemical synthesis
Sulfonamides / metabolism
Sulfonamides / pharmacology*

Substances

Antineoplastic Agents
Coumarins
Phosphoinositide-3 Kinase Inhibitors
Pyrazoles
Sulfonamides