Fluorinated quinazolinones as potential radiotracers for imaging kinesin spindle protein expression

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• 作者：Jason P. Holland^a ; ^b ; ^{holland.jason@mgh.harvard.edu} ; Michael W. Jones^c ; Susan Cohrs^d ; Roger Schibli^b ; ^d ; Eliane Fischer^d ; ^{eliane.fischer@psi.ch}
• 关键词：Quinazolinone ; Kinesin spindle protein ; Mitosis ; Fluorine ; Allosteric inhibitors
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2013
• 出版时间：15 January, 2013
• 年：2013
• 卷：21
• 期：2
• 页码：496-507
• 全文大小：1134 K

文摘

Anti-mitotic anti-cancer drugs offer a potential platform for developing new radiotracers for imaging proliferation markers associated with the mitosis-phase of the cell-cycle. One interesting target is kinesin spindle protein (KSP)¡ªan ATP-dependent motor protein that plays a vital role in bipolar spindle formation. In this work we synthesised a range of new fluorinated-quinazolinone compounds based on the structure of the clinical candidate KSP inhibitor, ispinesib, and investigated their properties in vitro as potential anti-mitotic agents targeting KSP expression. Anti-proliferation (MTT and BrdU) assays combined with additional studies including fluorescence-assisted cell sorting (FACS) analysis of cell-cycle arrest confirmed the mechanism and potency of these biphenyl compounds in a range of human cancer cell lines. Additional studies using confocal fluorescence microscopy showed that these compounds induce M-phase arrest via monoaster spindle formation. Structural studies revealed that compound 20-(R) is the most potent fluorinated-quinazolinone inhibitor of KSP and represents a suitable lead candidate for further studies on designing ¹⁸F-radiolabelled agents for positron-emission tomography (PET).