Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Queens, NY 11439, USA.
Eur J Med Chem. 2012 Apr;50:264-73. doi: 10.1016/j.ejmech.2012.02.001. Epub 2012 Feb 9.
We have demonstrated that quinazolin-4(3H)-one, a nicotinamide (NI) mimic with PARP-1 inhibitory activity in the high micromolar range (IC(50) = 5.75 μM) 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 IC(50) value of 0.76 μM. 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, IC(50) = 0.4 μM] in the present study. Compound 31 inhibited the proliferation of Brca1-deficient cells with an IC(50) value of 49.0 μM 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.
我们已经证明，烟酰胺（NI）类似物喹唑啉-4（3H）-1 酮（PARP-1 抑制剂，在高微摩尔范围内的 IC50 为 5.75 μM）可以转化为具有仅稍高分子量的高度活性衍生物。方便的一到两个合成步骤使我们能够在喹唑啉-4（3H）-1 酮支架的 2-、5-至 8-位探索广泛的 SAR。发现 2-和 8-位的取代基最有利于改善 PARP-1 抑制作用。8-位的氨基导致化合物 22 的 IC50 值为 0.76 μM。在本研究中，8-氨基取代基与 2-位的额外甲基取代基的组合提供了最有效的化合物 31[8-氨基-2-甲基喹唑啉-4（3H）-1 酮，IC50 值为 0.4 μM]。化合物 31 以 49.0 μM 的 IC50 值抑制了 BRCA1 缺陷细胞的增殖，对野生型细胞具有 >10 倍的选择性。这些衍生物在 PARP-1 活性部位的结合模型进一步支持了 SAR 数据，并将有助于未来的先导优化工作。
