Design, synthesis and 3D-QSAR analysis of novel thiopyranopyrimidine derivatives as potential antitumor agents inhibiting A549 and Hela cancer cells

Eur J Med Chem. 2020 Jan 1:185:111809. doi: 10.1016/j.ejmech.2019.111809.

Bingbing Zhao ¹, Chengwu Zhao ², Xiaohan Hu ³, Shan Xu ⁴, Zhou Lan ³, Yuping Guo ³, Zunhua Yang ⁵, Wufu Zhu ⁶, Pengwu Zheng ⁷

Affiliations

1 Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi, 330013, China; College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, China.
2 Department of Sports Medicine, The First Hospital of Jilin University, 71 Xinmin Road, Changchun, Jilin, 130021, China.
3 Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi, 330013, China.
4 Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi, 330013, China. Electronic address: shanxu9891@126.com.
5 College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, China.
6 Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi, 330013, China. Electronic address: zhuwufu-1122@163.com.
7 Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi, 330013, China. Electronic address: zhengpw@126.com.

PMID: 31683104 DOI: 10.1016/j.ejmech.2019.111809

Abstract

Four series of thiopyranopyrimidine AZD9291 derivatives containing acrylamide structure were designed, synthesized and evaluated for their antiproliferative activity against A549 and Hela Cancer cells. Most of the compounds exhibited excellent antiproliferative activity against A549 cells. Moreover, the compounds with indole ring fluorine substituted exhibited better antiproliferative activity against Hela cells. The most promising compound 23g exhibited excellent enzymatic inhibitory activity and selectivity for EGFR^L858R/T790M double mutations. The IC₅₀ value against EGFR^L858R/T790M kinase was 16 nM. The compound 23g inhibits selectively against the mutated form of EGFR, with the selectivity more than 125-fold. Furthermore, compound 23g also inhibited A549 cells, Hela cells and H1975 cells proliferation at a low concentration, and the IC₅₀ values were 0.057 μM, 0.104 μM and 0.916 μM, respectively. To further investigate the QSARs of thiopyranopyrimidine derivatives, the CoMFA (q [2] = 0.765, r² = 0.965) and CoMSIA (q [2] = 0.875, r² = 0.956) models on Hela Cancer cells were established. The generated 3D-QSAR model was validated to be reliable and can be used for further design and optimization of novel and selective EGFR inhibitors.

Keywords

3D-QSAR; CoMFA; CoMSIA; EGFR; Inhibitor; Thiopyranopyrimidine.

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