title: Synthesis and biological evaluation of novel oxindole-based RTK inhibitors as anti-cancer agents.
abstract: Given that receptor tyrosine kinases (RTKs) have emerged as key regulators of all aspects of cancer development, including proliferation, invasion, angiogenesis and metastasis, the RTK family represents an important therapeutic target for anti-cancer drug development. Oxindole structure has been used in RTK inhibitors such as SU4984 and intedanib. In this study, two series of new heterocyclic compounds containing oxindole scaffold have been designed and synthesized, and their inhibitory activity against the proliferation of nine cancer cell lines has been evaluated. Among them, compounds 9a and 9b displayed the strongest anti-proliferative activity with the IC50s below 10μM. Flow cytometric analysis showed that the compounds 9a and 9b dose-dependently arrested the cell cycle at G0/G1 phase. Although the leading compounds SU4984 and intedanib targets FGFR1, the kinase activity test revealed that these compounds only showed slight inhibitory activity on FGFR1 kinase. Further enzymatic test aided by molecular docking simulation in the ATP-binding site demonstrated that 9a and 9b are potent inhibitors of c-Kit kinase. These compounds are worthy of further evaluation as anticancer agents.
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Gaozhi
authors.initials: G
authors.lastname: Chen
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Qiaoyou
authors.initials: Q
authors.lastname: Weng
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Fu
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Pengtian
authors.initials: P
authors.lastname: Yu
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Li
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: HuajieZhang2014@163.com.
authors.forename: Huajie
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: wzmcliangguang@163.com.
authors.forename: Guang
authors.initials: G
authors.lastname: Liang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism; D062105:Molecular Docking Simulation; D000078183:Oxindoles; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011758:Pyrroles / Q000737:chemistry / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077210:Sunitinib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D000078183:Oxindoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; C022960:2-oxindole; D020794:Receptor Protein-Tyrosine Kinases; D000077210:Sunitinib
keywords: Anticancer drug; Chemical synthesis; Drug design; Oxindole; Receptor tyrosine kinase inhibitor