title: Structure and anti-proliferation function of 5,5-diphenyl-2-thiohydantoin (DPTH) derivatives in vascular endothelial cells.
abstract: Previously, we identified DPTH, an analogue of antiepileptic drug phenytoin (5,5-diphenylhydantoin, DPT), capable of retarding the cell cycle in the human vascular endothelial cells. Our data suggest that DPTH inhibits human umbilical venous endothelial cells (HUVEC) proliferation by increasing the level of p21 protein, which in turn inhibits the activities of cyclin-dependent kinase (CDK)2 and CDK4, and finally interrupts the cell cycle. To search chemicals with more potency in anti-angiogenic activity, we designed and synthesized several chemical compounds based on the structure-activity relationship consideration. We evaluated the anti-angiogenic activity of these compounds by examining their effects on DNA synthesis, cell number, p21 induction and capillary-like tube formation. Our results showed that introduction of side chain containing an aromatic ring structure with right spatial arrangement at sulfur atom of DPTH enhanced the anti-angiogenic activity in HUVEC.
authors.affiliation: Department of Ophthalmology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan; Fu-Jen Catholic University, School of Medicine, Taipei, Taiwan.
authors.forename: Cheng-Kuo
authors.initials: CK
authors.lastname: Cheng
authors.forename: Jender
authors.initials: J
authors.lastname: Wu
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.forename: Tong-Sheng
authors.initials: TS
authors.lastname: Lee
authors.forename: Shuo-Jhen
authors.initials: SJ
authors.lastname: Kang
authors.forename: Ming-Thau
authors.initials: MT
authors.lastname: Sheu
authors.forename: Wen-Sen
authors.initials: WS
authors.lastname: Lee
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects*; D006801:Humans; D015394:Molecular Structure; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010672:Phenytoin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013867:Thiohydantoins / Q000737:chemistry / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D020533:Angiogenesis Inhibitors; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D013867:Thiohydantoins; C073336:diphenylthiohydantoin; D010672:Phenytoin