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

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Abstract

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.

Graphical abstract

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.

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Acknowledgments

The authors thank the State Key New Drug Development Program (contract Grant Nos. 2008ZX09101-011, 2012ZX09101103). The authors also thank BioPredict, Inc. for allowing the use of their software BioCompare, BioDock and BioInterpreter in modeling.

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