title: Design, synthesis and evaluation of tetrahydroisoquinolines as new kinesin spindle protein inhibitors.
abstract: In this study, a series of tetrahydroisoquinolines have been synthesized and identified as novel kinesine spindle protein (KSP) inhibitors based on the pharmacophore we have mapped and the crystal structure of monastrol bound to the target protein. The KSP inhibitory activities of all the designed compounds were tested using cloned Human KSP protein. All thirteen compounds were more potent than the control, monastrol, in Human KSP protein adenosine triphosphatase (ATPase) assays. Three compounds (1b, 1g, 1h) exhibited over 100 times higher potency than monastrol. Cytotoxic results in vitro by MTT method indicated that nine of these compounds (1a, 1b, 1c, 1d, 1e, 1g, 1h, 1j, 1k) were more active than monastrol. In particular, compounds 1b and 1g, each of which contains a hydrophilic group on the side chain at the 2-position, exhibited excellent cell-killing activities against HepG2 cells.
authors.affiliation: Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, P. R. China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Jiang
authors.forename: Qidong
authors.initials: Q
authors.lastname: You
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.forename: Wutong
authors.initials: W
authors.lastname: Wu
authors.forename: Qinglong
authors.initials: Q
authors.lastname: Guo
authors.forename: Jiwang
authors.initials: J
authors.lastname: Chern
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
authors.forename: Mengling
authors.initials: M
authors.lastname: Chen
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D045744:Cell Line, Tumor; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007202:Indicators and Reagents; D016547:Kinesins / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D008968:Molecular Conformation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D013778:Tetrazolium Salts; D013844:Thiazoles
chemical_list: D000970:Antineoplastic Agents; D007202:Indicators and Reagents; C470243:KIF11 protein, human; D044005:Tetrahydroisoquinolines; D013778:Tetrazolium Salts; D013844:Thiazoles; D000251:Adenosine Triphosphatases; D016547:Kinesins; C022616:thiazolyl blue