Synthesis and biological evaluation of crown ether fused quinazoline analogues as potent EGFR inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2012-10, Vol.22 (19), p.6301-6305
• Main Authors: Hu, Shaojing, Xie, Guojian, Zhang, Don X., Davis, Charles, Long, Wei, Hu, Yunyan, Wang, Fei, Kang, Xinshan, Tan, Fenlai, Ding, Lieming, Wang, Yinxiang
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell Proliferation - drug effects; Crown ether fused anilinoquinazoline; Crown Ethers - chemistry; Dose-Response Relationship, Drug; EGFR inhibitor; epidermal growth factor receptors; Humans; Indexing in process; Medical sciences; Mice; Models, Molecular; Molecular Structure; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - pathology; pharmacokinetics; Pharmacology. Drug treatments; phosphorylation; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - pharmacology; Quinazolines - administration & dosage; Quinazolines - chemical synthesis; Quinazolines - pharmacology; Rats; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - metabolism; Structure-Activity Relationship; Synthesis; tyrosine; Xenograft Model Antitumor Assays
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.06.067

A series of crown ether fused anilinoquinazolines have been synthesized and evaluated for EGFR inhibition. Compound 12k (Icotinib) showed excellent enzymatic and cellular activities against EGFR. Icotinib is in phase III clinical trials currently. Crown ether fused anilinoquinazoline analogues were synthesized as novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Representative compounds showed potent and selective EGFR inhibitory activities in an in vitro EGFR kinase assay and an EGFR-mediated intracellular tyrosine phosphorylation assay. The synthesis and preliminary biological, physical, and pharmacokinetic evaluation of these fused quinazoline compounds is reported.