Design, synthesis and biological activity of novel 2,3,4,5-tetra-substituted thiophene derivatives as PI3Kα inhibitors with potent antitumor activity

被引：11

作者：

Liao, Weike ^{[1
]}

Wang, Zhongyuan ^{[2
]}

Han, Yufei ^{[3
]}

Qi, Yinliang ^{[3
]}

Liu, Jiaan ^{[5
]}

Xie, Juan ^{[2
]}

Tian, Ye ^{[3
]}

Lei, Qiancheng ^{[1
]}

Chen, Rui ^{[1
]}

Sun, Ming ^{[3
]}

Tang, Lei ^{[1
]}

Gong, Guowei ^{[4
]}

Zhao, Yanfang ^{[3
]}

机构：

[1] Guizhou Med Univ, Guizhou Prov Engn Technol Res Ctr Chem Drug R&D, State Key Lab Funct & Applicat Med Plants, Guiyang 550004, Peoples R China

[2] Guizhou Prov Peoples Hosp, Dept Pharm, Guiyang 550002, Peoples R China

[3] Shenyang Pharmaceut Univ, Minist Educ, Key Lab Struct Based Drug Design & Discovery, 103 Wenhua Rd, Shenyang 110016, Peoples R China

[4] Zunyi Med Univ, Dept Bioengn, Zhuhai Campus, Zhuhai 519041, Guangdong, Peoples R China

[5] Univ Massachusetts Amherst, Dept Chem, Amherst, MA 01003 USA

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 197卷

基金：

中国国家自然科学基金;

关键词：

PI3K alpha; Antiproliferative activities; Synthesis; 2,3,4,5-Tetra-substituted thiophene derivatives; PI3K INHIBITORS; DISCOVERY; PATHWAY; NVP-BYL719; TARGET;

D O I：

10.1016/j.ejmech.2020.112309

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Using a rational design strategy for isoform-selective inhibition of PI3K alpha, two series of novel 2,3,4,5-tetra-substituted thiophene derivatives containing either diaryl urea or N-Acylarylhydrazone scaffold were designed and synthesized. The most promising compound 12k was demonstrated to bear nanomolar PI3K alpha inhibitory potency with 12, 28, 30, 196-fold selectivity against isoforms beta, gamma, delta and mTOR. Besides, it also showed good developability profiles in cell-based proliferation against a panel of human tumor cells as well as ADME assays. We herein report on their design, synthesis, SAR and potential developability properties. (C) 2020 Elsevier Masson SAS. All rights reserved.

引用

页数：14

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