Development of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates bearing sulfonylpiperazine as antitumor inhibitors targeting PI3Kα

Eur J Med Chem. 2019 Nov 15:182:111630. doi: 10.1016/j.ejmech.2019.111630.

Yong Yin ¹, Shao Sha ², Xun Wu ², She-Feng Wang ², Fang Qiao ², Zhong-Cheng Song ³, Hai-Liang Zhu ⁴

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, PR China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210093, PR China.
2 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210093, PR China.
3 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210093, PR China; School of Chemistry & Environmental Engineering, Jiangsu University of Technology, 1801 Zhongwu Rd., Changzhou, Jiangsu, 213001, China. Electronic address: songzhongcheng@jsut.edu.cn.
4 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210093, PR China. Electronic address: zhuhl@nju.edu.cn.

PMID: 31446244 DOI: 10.1016/j.ejmech.2019.111630

Abstract

PI3K signal pathway plays a vital role in cellular functions and becomes an attractive approach for Cancer therapy. Herein, a new series of novel chromeno[4,3-c]pyrazol-4(2H)-one derivatives bearing sulfonylpiperazine based on the PI3K inhibitors and our previous research. They were screened for their PI3K inhibitory activities and Anticancer effects in vitro. Biological studies indicated that compound 7m revealed the remarkable antiproliferative activity (IC₅₀ ranging from 0.03 to 0.09 μM) against four Cancer cell lines (A549, Huh7, HL60 and HCT-116). Besides, compound 7m displayed a certain selective for PI3Kα (IC₅₀ = 0.009 μM) over PI3Kβ, γ and δ, and meanwhile, it can remarkable decreased the expression level of p-Akt (Ser473) and p-S6K. In addition, compound 7m could not only induce HCT-116 cell arrest at G1 phase in a dose-dependent manner, but also induce cell Apoptosis via upregulation of Bax and cleaved-caspase 3/9, and downregulation of Bcl-2. Besides, compound 7m can remarkably inhibit the growth of tumor in vivo. The above results suggested that compound 7m could be considered as a promising PI3Kα Inhibitor.

Keywords

Antitumor; PI3Kα inhibitor; Sulfonylpiperazine; chromeno[4,3-c]pyrazol-4(2H)-one derivates.

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