Format:
Online-Ressource
ISSN:
1612-1880
Content:
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.
In:
volume:10
In:
number:4
In:
year:2013
In:
pages:538-555
In:
extent:18
In:
Chemistry & biodiversity, Zürich : Wiley-VHCA, [2004]-, 10, Heft 4 (2013), 538-555 (gesamt 18), 1612-1880
Language:
English
DOI:
10.1002/cbdv.201200400
URN:
urn:nbn:de:101:1-2023021805000971219643
URL:
https://doi.org/10.1002/cbdv.201200400
URL:
https://nbn-resolving.org/urn:nbn:de:101:1-2023021805000971219643
URL:
https://d-nb.info/1281326828/34
URL:
https://doi.org/10.1002/cbdv.201200400