Bis(hetero)aryl derivatives as unique kinesin spindle protein inhibitors

Synthesis of 4-(4-tert-butylphenyl)pyridine analogues as kinesin spindle protein (KSP) inhibitors, SAR, cytotoxicity and mitotic arrest in HeLa cells are described. Interestingly, PVZB1194 showed potent KSP inhibition only in the presence of microtubules and distinct KSP localization from a known KSP inhibitor S-trytylcysteine analogue in mitosis. The observations would have resulted from a different molecular mechanism of KSP inhibition and suggest a novel biological regulation for KSP in mitosis.

Graphical abstractSynthesis of 4-(4-tert-butylphenyl)pyridine (1) analogues as KSP inhibitor, SAR, cytotoxicity and mitotic arrest in HeLa cells are described. Distinct KSP distribution by different chemotypes of KSP inhibitor is also reported.Figure optionsDownload full-size imageDownload as PowerPoint slide