Design, synthesis and biological activities of novel oxazolo[4,5-g]quinazolin-2(1H)-one derivatives as EGFR inhibitors

Siyuan Yin; Liliang Zhou; Jinsheng Lin; Lingjing Xue; Can Zhang

doi:10.1016/j.ejmech.2015.07.008

Design, synthesis and biological activities of novel oxazolo[4,5-g]quinazolin-2(1H)-one derivatives as EGFR inhibitors

Eur J Med Chem. 2015 Aug 28:101:462-75. doi: 10.1016/j.ejmech.2015.07.008. Epub 2015 Jul 10.

Authors

Siyuan Yin¹, Liliang Zhou¹, Jinsheng Lin¹, Lingjing Xue², Can Zhang³

Affiliations

¹ State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
² State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China. Electronic address: xuelingjing65@163.com.
³ State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China. Electronic address: zhangcan@cpu.edu.cn.

PMID: 26188620
DOI: 10.1016/j.ejmech.2015.07.008

Abstract

A series of oxazolo[4,5-g]quinazolin-2(1H)-one derivatives employing Erlotinib as lead compound were synthesized and evaluated for their EGFR inhibition activity. These compounds having variation at the 1 and 8-position, included ether and esters hydrophilic side-chain and aromatic head fragment, respectively. All these compounds were evaluated by EGFR inhibition and two anti-proliferation assays in vitro. Four compounds were found more potent than Erlotinib in EGFR-TK assay. Furthermore, compounds 18, 42 and 50 also had good to excellent anti-proliferation activity against human epidermoid cancer cell line (KB) and renal cell carcinoma cell line (A498). Finally, compound 50 presented remarkably higher inhibition efficacy towards tumor growth than Erlotinib in a mouse lewis lung cancer (LLC) xenograft model. Furthermore, compound 50 displayed the most distinguished effect on extending the survival period of the tumor-bearing mice.

Keywords: Docking; EGFR inhibitor; Oxazolo[4,5-g]quinazolin-2(1H)-one scaffold; Protein tyrosine kinases (PTK); SAR.

Publication types

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

MeSH terms

Animals
Antineoplastic Agents / administration & dosage
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Benzoxazoles / chemical synthesis
Benzoxazoles / chemistry
Benzoxazoles / pharmacology*
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
Mice
Mice, SCID
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / pathology
Quinazolines / chemical synthesis
Quinazolines / chemistry
Quinazolines / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Benzoxazoles
Quinazolines
ethyl 4-(8-(3-hydroxyphenylamino)-2-oxooxazolo(4,5-g)quinazolin-1(2H)-yl)butanoate
ErbB Receptors