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.

References and notes (16)

  • (a)Chen, L.; Ding, Q.; Gillespie, P.; Kim, K.; Lovey, A. J.; McComas, W. M.; Mullin, J. G., Jr.; Perrotta, A. PCT Int....(b)Chu, X.; Ding, Q.; Jiang, N.; Kim, K.; Lovey, A. J.; McComas, W. M.; Mullin, J. G., Jr.; Tilley, J. W. PCT Int....
  • (a)Binnun, E.; Johnson, S. G.; Connolly, P. J.; Middleton, S. A.; Moreno-Mazza, S. J.; Lin, R.; Pandey, N. B.; Wetter,...(b)Lin, R.; Johnson S. G.; Connolly, P. J.; Wetter, S. K.; Binnun, E.; Hughes, T. V.; Murray, W. V.; Adams, M.;...
  • D. Wobig

    Liebigs Ann. Chem.

    (1989)
  • Q. Zhao et al.

    Lung Cancer

    (2011)
    Y. Sun et al.

    J. Clin. Oncol.

    (2011)
  • S. Garofalo et al.

    Expert Opin. Ther. Patents

    (2008)
    M. Srinivasan et al.

    Clin. Biochem.

    (2004)
    P. Traxler

    Expert Opin. Ther. Targets

    (2003)
    G.S. Cockerill et al.

    Curr. Top. Med. Chem.

    (2002)
    Y. Yarden et al.

    Nat. Rev. Mol. Cell Biol.

    (2001)
    S. Teman et al.

    J. Clin. Oncol.

    (2007)
    L. Vecchione et al.

    Exp. Cell Res.

    (2011)
    R. Saxena et al.

    Med. Res. Rev.

    (2012)
    G.M. Stella et al.

    Respir Med

    (2012)
    W. Han et al.

    Cancer Lett.

    (2012)
  • F. Barlesi et al.

    Fundam. Clin. Pharmacol.

    (2005)
    C.L. Arteaga et al.

    Curr. Opin. Oncol.

    (2001)
    A.J. Baker et al.

    Bioorg. Med. Chem. Lett.

    (1911)
    A. D’Incecco et al.

    Expert Opin. Drug Saf.

    (2011)
  • K.N. Ganjoo et al.

    Biol. Targets Ther.

    (2007)
    L. Paz-Ares

    Lancet Oncol.

    (2012)
  • L. Kopper

    Pathol. Oncol. Res.

    (2008)
    S. Dhillon et al.

    Drugs

    (2007)
    H.A. Burris et al.

    J. Clin. Oncol.

    (2005)
    F.L. Opdam et al.

    Oncologist

    (2012)
There are more references available in the full text version of this article.

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