title: Synthesis, biological evaluation and molecular docking studies of flavone and isoflavone derivatives as a novel class of KSP (kinesin spindle protein) inhibitors.
abstract: The kinesin spindle protein (KSP) is involved in the formation of bipolar mitotic spindle during cell division and it becomes a new target to overcome the neurotoxicity of MTs inhibitors. A series of flavone and isoflavone derivatives (1a-7c) have been designed, synthesized and evaluated as potential KSP inhibitors. Among them, 2c displayed the most potent inhibitory activity in vitro, which inhibited the growth of MCF-7 and Hela cell lines with IC50 values of 4.8 and 4.3 μM, respectively, and also exhibited significant KSP inhibitory activity (IC₅₀ = 0.023 μM). The new compounds can induce irregular monoastral spindles, the characteristic phenotype for KSP inhibiting agents. Docking simulation was further performed to determine the probable binding model.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China.
authors.forename: Jing-Jun
authors.initials: JJ
authors.lastname: Dong
authors.forename: Qing-Shan
authors.initials: QS
authors.lastname: Li
authors.forename: Zhi-Peng
authors.initials: ZP
authors.lastname: Liu
authors.forename: Shu-Fu
authors.initials: SF
authors.lastname: Wang
authors.forename: Meng-Yue
authors.initials: MY
authors.lastname: Zhao
authors.forename: Yong-Hua
authors.initials: YH
authors.lastname: Yang
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Wang
authors.forename: Hai-Liang
authors.initials: HL
authors.lastname: Zhu
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047309:Flavones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D007529:Isoflavones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D061986:MCF-7 Cells; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D047309:Flavones; D007529:Isoflavones; C470243:KIF11 protein, human; D016547:Kinesins; C043562:flavone
keywords: Antimitotic; Flavone; Isoflavone; KSP; Kinesin inhibitor; Monoastral spindles