title: Design and synthesis of Lapatinib derivatives containing a branched side chain as HER1/HER2 targeting antitumor drug candidates.
abstract: 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.
authors.affiliation: 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.
authors.forename: Aifeng
authors.initials: A
authors.lastname: Lyu
authors.affiliation: Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Fang
authors.affiliation: Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China. Electronic address: sgou@seu.edu.cn.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Gou
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000187:drug effects*; D005434:Flow Cytometry; D006801:Humans; D066298:In Vitro Techniques; D000077341:Lapatinib; D062105:Molecular Docking Simulation; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C512478:EGFR protein, human; C508053:ERBB2 protein, human
keywords: Antitumor; HER1/HER2 targeting; Lapatinib derivatives; Tyrosine kinase inhibitors