title: Synthesis and biological evaluation of 4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-6-(3-substituted-phenoxy)pyrimidines as dual EGFR/ErbB-2 kinase inhibitors.
abstract: 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-fluorobenzyloxy)anilino]-6-(3-acrylamidophenoxy)pyrimidine (6), 4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-6-(3-cyanoacetamidophenoxy)pyrimidine (9), 4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-6-{3-[6-(4-amino)pyrimidinyl]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 (IC(50)=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 IC(50) value of 6 being 3.25 μM for A431 and 0.89 μM for SKOV-3, as for 11, 4.24 μM for A431 and 0.71 μM for SKOV-3, respectively. Docking study was also performed to determine the possible binding model.
authors.affiliation: Shanghai Key Laboratory of Functional Materials Chemistry, Research Centre of Analysis and Test, East China University of Science and Technology, Shanghai 200237, PR China.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Li
authors.forename: Chunying
authors.initials: C
authors.lastname: Guo
authors.forename: Hongli
authors.initials: H
authors.lastname: Zhao
authors.forename: Yun
authors.initials: Y
authors.lastname: Tang
authors.forename: Minbo
authors.initials: M
authors.lastname: Lan
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D003198:Computer Simulation; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D018719:Erb-b2 Receptor Tyrosine Kinases; C030986:pyrimidine