Design and synthesis of Lapatinib derivatives containing a branched side chain as HER1/HER2 targeting antitumor drug candidates
- Eur J Med Chem. 2014 Nov 24:87:631-42. doi: 10.1016/j.ejmech.2014.10.006.
- 1. Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China; Jiangsu Hansoh Pharmceutical Corporation, Lianyungang 222000, China.
- 2. Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.
- 3. Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China. Electronic address: [email protected].
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 2i also indicated it had a good performance on both absorption and elimination profiles.