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

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Li S, Guo C, Zhao H, Tang Y, Lan M

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

Bioorg Med Chem. 2012 Jan 15;20(2):877-85. doi: 10.1016/j.bmc.2011.11.056. Epub 2011 Dec 3.

PubMed ID
22182581 [ View in PubMed
]
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 muM for A431 and 0.89 muM for SKOV-3, as for 11, 4.24 muM for A431 and 0.71 muM for SKOV-3, respectively. Docking study was also performed to determine the possible binding model.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
LapatinibEpidermal growth factor receptorIC 50 (nM)9N/AN/ADetails
LapatinibReceptor tyrosine-protein kinase erbB-2IC 50 (nM)10.3N/AN/ADetails