title: Novel 6-methoxycarbonyl indolinones bearing a pyrrole Mannich base moiety as angiokinase inhibitors.
abstract: Inhibition of tumor angiogenesis through simultaneously disturbing vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) mediated signaling pathways is a well-established approach in intervention of tumor. A series of 6-methoxycarbonyl indolinones bearing a pyrrole Mannich base moiety were synthesized and evaluated as potent angiokinase inhibitors. Compound 8a demonstrated favorable enzymatic activity against all subtypes of VEGFR and PDGFR. Also, it potently suppressed proliferation of HT-29 cells by inducing apoptosis. Compound 8a has emerged as a promising lead compound for development of angiokinase inhibitors targeting VEGFR and PDGFR.
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenyang 110016, PR China. Electronic address: qinmingze001@126.com.
authors.forename: Mingze
authors.initials: M
authors.lastname: Qin
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenyang 110016, PR China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Yan
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenyang 110016, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China.
authors.forename: Haotian
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenyang 110016, PR China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenyang 110016, PR China.
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenyang 110016, PR China. Electronic address: gongpinggp@126.com.
authors.forename: Ping
authors.initials: P
authors.lastname: Gong
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008352:Mannich Bases / Q000737:chemistry*; D062105:Molecular Docking Simulation; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000187:drug effects*; D011758:Pyrroles / Q000737:chemistry*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D007211:Indoles; D008352:Mannich Bases; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D011494:Protein Kinases; D020797:Receptor, Platelet-Derived Growth Factor beta
keywords: 6-Methoxycarbonyl indolinones; Angiokinase inhibitors; Antitumor activity; Conformational restriction strategy