Design and synthesis of Lapatinib derivatives containing a branched side chain as HER1/HER2 targeting antitumor drug candidates
作者:Aifeng Lyu、Lei Fang、Shaohua Gou
DOI:10.1016/j.ejmech.2014.10.006
日期:2014.11
A series of Lapatinib derivatives were designed and prepared by changing the straight alkyl side chain of Lapatinib into a branched one. ELISA assay and western blot analysis showed that these derivatives can significantly inhibit HER1/HER2 as well as their downstream signal transduction proteins. In vitro cytotoxicity assay revealed that these compounds had potent cytotoxic effect against the HER1/HER2-overexpressing cancer cells. A representive compound, 2i, showed potent in vivo antitumor activity comparable to Lapatinib, which was found to block the cell-cycle progression of BT474 cells in the G1 phase causing tumor cell apoptosis in the flow cytometry study. Moreover, the pharmacokinetic investigation on 21 also indicated it had a good performance on both absorption and elimination profiles. (c) 2014 Elsevier Masson SAS. All rights reserved.