Synthesis and SAR optimization of quinazolin-4(3H)-ones as poly(ADP-ribose)polymerase-1 inhibitors

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• 作者：Shridhar S. Kulkarni¹ ; Satyakam Singh¹ ; Janki R. Shah ; Woon-Kai Low ; Tanaji T. Talele ; ^{talelet@stjohns.edu}
• 关键词：Quinazolinone ; PARP-1 ; BRCA1 ; p53 ; Docking
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：April, 2012
• 年：2012
• 卷：50
• 期：Complete
• 页码：264-273
• 全文大小：834 K

文摘

We have demonstrated that quinazolin-4(3H)-one, a nicotinamide (NI) mimic with PARP-1 inhibitory activity in the high micromolar range (IC₅₀?=?5.75?¦ÌM) could be transformed into highly active derivatives with only marginal increase in molecular weight. Convenient one to two synthetic steps allowed us to explore extensive SAR at the 2-, and 5- through 8-positions of the quinazolin-4(3H)-one scaffold. Substitutions at the 2- and 8-positions were found to be most favorable for improved PARP-1 inhibition. The amino group at 8-position resulted in compound 22 with an IC₅₀ value of 0.76?¦ÌM. Combination of the 8-amino substituent with an additional methyl substituent at the 2-position provided the most potent compound 31 [8-amino-2-methylquinazolin-4(3H)-one, IC₅₀?=?0.4?¦ÌM] in the present study. Compound 31 inhibited the proliferation of Brca1-deficient cells with an IC₅₀ value of 49.0?¦ÌM and displayed >10-fold selectivity over wild type counterparts. Binding models of these derivatives within the active site of PARP-1 have further supported the SAR data and will be useful for future lead optimization efforts.