Synthesis and biological evaluation of 4-[3-chloro-4-(3-fluorobenzyloxy) anilino]-6-(3-substituted-phenoxy)pyrimidines as dual EGFR/ErbB-2 kinase inhibitors

A series of 4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-6-(3-substituted-phenoxy)pyrimidine derivatives were elaborately designed based on the skeleton of Lapatinib, and evaluated for their potential to inhibit epidermal growth factor receptor (EGFR) and ErbB-2 tyrosine kinase activities and antiproliferative activities against A431 and SKOV-3 cell lines. Among these synthesized pyrimidine derivatives, 4-[3-chloro-4-(3-fluorob enzyloxy)anilino]-6-(3-acrylamidophenoxy)pyrimidine (6), 4-13-chloro-4-(3-fluorobenzyloxy)anilino]-6-(3cyanoacetamidophenoxy)pyrimidine (9), 4-[3-chloro-4-(3-fluorobenzyloxy)anilino)-6-(3-[6-(4-amino)pyri midinyl]amino) phenoxy)pyrimidine (11) and 4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-6-(3-phenoxyacetamidophenoxy)pyrimidine (14) could significantly inhibit dual EGFR/ErbB-2 kinase activities (IC50 = 37/29 nM, 48/38 nM, 61/42 nM, 65/79 nM, respectively). And compounds 6 and 11 also showed the most potent antiproliferative activities in vitro, with the IC50 value of 6 being 3.25 mu M for A431 and 0.89 mu M for SKOV-3, as for 11,4.24 mu M for A431 and 0.71 mu M for SKOV-3, respectively. Docking study was also performed to determine the possible binding model. (C) 2011 Elsevier Ltd. All rights reserved.