Design, synthesis, antiproliferative activity and docking studies of quinazoline derivatives bearing 2,3-dihydro-indole or 1,2,3,4-tetrahydroquinoline as potential EGFR inhibitors

Yiqiang OuYang; Wensheng Zou; Liang Peng; Zunhua Yang; Qidong Tang; Mengzi Chen; Shuang Jia; Hong Zhang; Zhou Lan; Pengwu Zheng; Wufu Zhu

doi:10.1016/j.ejmech.2018.05.006

Design, synthesis, antiproliferative activity and docking studies of quinazoline derivatives bearing 2,3-dihydro-indole or 1,2,3,4-tetrahydroquinoline as potential EGFR inhibitors

Eur J Med Chem. 2018 Jun 25:154:29-43. doi: 10.1016/j.ejmech.2018.05.006. Epub 2018 May 9.

Authors

Yiqiang OuYang¹, Wensheng Zou¹, Liang Peng¹, Zunhua Yang², Qidong Tang¹, Mengzi Chen¹, Shuang Jia¹, Hong Zhang¹, Zhou Lan¹, Pengwu Zheng³, Wufu Zhu⁴

Affiliations

¹ Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, 330013, China.
² College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, China.
³ Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, 330013, China. Electronic address: zhengpw@126.com.
⁴ Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, 330013, China. Electronic address: zhuwufu-1122@163.com.

PMID: 29775935
DOI: 10.1016/j.ejmech.2018.05.006

Abstract

Eight series of quinazoline derivatives bearing 2,3-dihydro-indole or 1,2,3,4-tetrahydroquinoline were designed, synthesized and evaluated for the IC₅₀ values against three cancer cell lines (A549, MCF-7 and PC-3). Most of the forty nine target compounds showed excellent antiproliferative activity against one or several cancer cell lines. The compound 13a showed the best activity against A549, MCF-7 and PC-3 cancer cell lines, with the IC₅₀ values of 1.09 ± 0.04 μM, 1.34 ± 0.13 μM and 1.23 ± 0.09 μM, respectively. Eight selected compounds were further selected to evaluated for the inhibitory activity against EGFR kinase. Three of them showed equal activity against EGFR kinase to positive control afatinib. AnnexinV-FITC, propidium iodide (PI) double staining and acridine orange single staining results indicated that the compound 13a could induce apoptosis of human lung cancer A549 cells.

Keywords: Antiproliferative activity; EGFR inhibitors; Quinazoline derivatives; Synthesis.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
ErbB Receptors / antagonists & inhibitors*
ErbB Receptors / metabolism
Humans
Indoles / chemistry
Indoles / pharmacology*
Molecular Docking Simulation
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Quinazolines / chemical synthesis
Quinazolines / chemistry
Quinazolines / pharmacology*
Quinolines / chemistry
Quinolines / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Indoles
Protein Kinase Inhibitors
Quinazolines
Quinolines
1,2,3,4-tetrahydroquinoline
ErbB Receptors