title: Design, synthesis, and biological evaluation of novel 3-pyrrolo[b]cyclohexylene-2-dihydroindolinone derivatives as potent receptor tyrosine kinase inhibitors.
abstract: A novel series of 3-pyrrolo[b]cyclohexylene-2-dihydroindolinone derivatives targeting VEGFR-2, PDGFR-β and c-Kit kinases were designed and synthesized. The molecular design was based on the SAR features of indolin-2-ones as kinase inhibitors. SAR study of the series allowed us to identify compounds possessing more potent inhibitory activities against the three kinases than sunitinb with IC50 values in the low nanomolar range in vitro. Additionally, some compounds also showed favorable antiproliferative activities against a panel of cancer cell lines (BXPC-3, T24, BGC, HEPG2 and HT29).
authors.affiliation: The College of Biotechnology and Pharmaceutical Engineering, Nanjing University of Technology, No. 30 Puzhu Road(S), Nanjing 211800, China; Jiangsu Simcere Pharmaceutical Co., Ltd, Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No. 699-18 Xuan Wu Avenue, Nanjing 210042, China. Electronic address: dinglei@simcere.com.
authors.forename: Lei
authors.initials: L
authors.lastname: Ding
authors.forename: Feng
authors.initials: F
authors.lastname: Tang
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.forename: Qiu
authors.initials: Q
authors.lastname: Jin
authors.forename: Han
authors.initials: H
authors.lastname: Shen
authors.forename: Ping
authors.initials: P
authors.lastname: Wei
mesh_terms: D006801:Humans; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D019073:HT29 Cells; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D017434:Protein Structure, Tertiary; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D005021:Ethylamines
chemical_list: D007211:Indoles; C057812:indoline; D047428:Protein Kinase Inhibitors; D019009:Proto-Oncogene Proteins c-kit; D020797:Receptor, Platelet-Derived Growth Factor beta; D040301:Vascular Endothelial Growth Factor Receptor-2; C570037:N-(2-(diethylamino)ethyl)-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H-indol-3-ylidene)-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; D005021:Ethylamines
keywords: 2-Dihydroindolinone derivatives; Antiproliferative; Inhibitor; Molecular docking; Receptor tyrosine kinase