title: Pyrrolidino Analogues of Gefitinib with Improved EGFR Inhibition, Cancer Cell Cytotoxicity, and Pharmacokinetic Properties.
abstract: The binding mode analysis of Gefitinib revealed that 6-propylmorpholino group (sidechain) shows no interactions due to its weak electron density. In order to modify the electron density of Gefitinib's sidechain, novel pyrrolidino analogs of Gefitinib where morpholino groups were replaced by substituted pyrrolidino groups were synthesized. Gefitinib derivatives with high electronegativity atoms or groups in the pyrrolidino moiety always exhibit high potent activity against EGFR and human cancer cell lines, A431, MDA-MB-231 and A549. Among these derivatives, 16 displayed the best pharmacokinetic properties that make it to be a promising candidate for developing drugs to replace Gefitinib.
authors.affiliation: School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing, 210094, China. fjk_003@163.com.
authors.forename: Jing-Kun
authors.initials: JK
authors.lastname: Fang
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Xu
authors.forename: Yingjun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Weihong
authors.initials: W
authors.lastname: Zhang
authors.forename: Bing
authors.initials: B
authors.lastname: Liu
authors.forename: Yu
authors.initials: Y
authors.lastname: Fang
authors.forename: Tengxiao
authors.initials: T
authors.lastname: Sun
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011759:Pyrrolidines; C512478:EGFR protein, human; D066246:ErbB Receptors