Synthesis and Evaluation of Biphenyl Compounds as Kinesin Spindle Protein Inhibitors |
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| Authors: | Jason P Holland Albert Kang Susan Cohrs Svetlana V Selivanova Selena Milicevic Sephton Thomas Betzel Daniel Frey Mara Wieser Rolf Jaussi Richard A Kammerer Roger Schibli Eliane Fischer |
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| Institution: | 1. 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, (phone: +1‐(617)‐726‐6107;2. fax: +1‐(617)‐726‐6165);3. Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zürich, CH‐8093 Zürich;4. Center for Radiopharmaceutical Sciences, Paul Scherrer Institute, CH‐5232 Villigen PSI, (phone: +41‐56‐310‐2857;5. fax: +41‐56‐310‐2849);6. Laboratory of Biomolecular Research, Paul Scherrer Institut, CH‐5232 Villigen PSI |
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| 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. |
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| Keywords: | Kinesin spindle protein Biphenyls Inhibitors Mitosis Antiproliferative activity Confocal fluorescence microscopy Density‐functional theory (DFT) |
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