title: Synthesis and evaluation of biphenyl compounds as kinesin spindle protein inhibitors.
abstract: Kinesin spindle protein (KSP), an ATP-dependent motor protein, plays an essential role in bipolar spindle formation during the mitotic phase (M phase) of the normal cell cycle. KSP has emerged as a novel target for antimitotic anticancer drug development. In this work, we synthesized a range of new biphenyl compounds and investigated their properties in vitro as potential antimitotic agents targeting KSP expression. Antiproliferation (MTT (=3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide)) assays, combined with fluorescence-assisted cell sorting (FACS) and Western blot studies analyzing cell-cycle arrest confirmed the mechanism and potency of these biphenyl compounds in a range of human cancer cell lines. Structural variants revealed that functionalization of biphenyl compounds with bulky aliphatic or aromatic groups led to a loss of activity. However, replacement of the urea group with a thiourea led to an increase in antiproliferative activity in selected cell lines. Further studies using confocal fluorescence microscopy confirmed that the most potent biphenyl derivative identified thus far, compound 7, exerts its pharmacologic effect specifically in the M phase and induces monoaster formation. These studies confirm that chemical scope remains for improving the potency and treatment efficacy of antimitotic KSP inhibition in this class of biphenyl compounds.
authors.affiliation: Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital, and Department of Radiology, Harvard Medical School, 55 Fruit St., White 427, Boston 02114, MA, USA. holland.jason@mgh.harvard.edu
authors.forename: Jason P
authors.initials: JP
authors.lastname: Holland
authors.forename: Albert
authors.initials: A
authors.lastname: Kang
authors.forename: Susan
authors.initials: S
authors.lastname: Cohrs
authors.forename: Svetlana V
authors.initials: SV
authors.lastname: Selivanova
authors.forename: Selena
authors.initials: S
authors.lastname: Milicevic Sephton
authors.forename: Thomas
authors.initials: T
authors.lastname: Betzel
authors.forename: Daniel
authors.initials: D
authors.lastname: Frey
authors.forename: Mara
authors.initials: M
authors.lastname: Wieser
authors.forename: Rolf
authors.initials: R
authors.lastname: Jaussi
authors.forename: Richard A
authors.initials: RA
authors.lastname: Kammerer
authors.forename: Roger
authors.initials: R
authors.lastname: Schibli
authors.forename: Eliane
authors.initials: E
authors.lastname: Fischer
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D050256:Antimitotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D045325:HCT116 Cells; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D061986:MCF-7 Cells; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000737:chemistry
chemical_list: D050256:Antimitotic Agents; D001713:Biphenyl Compounds; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D000255:Adenosine Triphosphate; D016547:Kinesins; D013890:Thiourea