Newcastle Cancer Centre at the Northern Institute for Cancer Research and School of Chemistry, Bedson Building, Newcastle University, Newcastle, NE1 7RU, UK.
Bioorg Med Chem Lett. 2011 Oct 1;21(19):5916-9. doi: 10.1016/j.bmcl.2011.07.084. Epub 2011 Aug 9.
Structure-activity relationships for the MDM2-p53 inhibitory activity of a series of A-ring substituted 2-N-benzyl-3-(4-chlorophenyl)-3-(1-(hydroxymethyl)cyclopropyl)methoxy)isoindolinones have been investigated, giving rise to compounds with improved potency over their unsubstituted counterparts. Isoindolinone A-ring substitution with a 4-chloro group for the 4-nitrobenzyl, 4-bromobenzyl and 4-cyanobenzyl derivatives (10a-c) and substitution with a 6-tert-butyl group for the 4-nitrobenzyl derivative (10j) were found to confer additional potency. Resolution of the enantiomers of 10a showed that potent MDM2-p53 activity resided in the (-)-enantiomer ((-)-10a; IC(50)=44 ± 6 nM). The cellular activity of key compounds has been examined in cell lines with defined p53 and MDM2 status. Compounds 10a and (-)-10a increase p53 protein levels, activate p53-dependent MDM2 and p21 transcription in MDM2 amplified cells, and show improved selectivity for growth inhibition in wild type p53 cell lines over the parent compound.
我们研究了一系列 A 环取代的 2-N-苄基-3-(4-氯苯基)-3-(1-(羟甲基)环丙基)甲氧基)异吲哚啉酮对 MDM2-p53 抑制活性的构效关系，得到了比未取代的同类物具有更高活性的化合物。异吲哚啉酮 A 环用 4-氯取代 4-硝基苄基、4-溴苄基和 4-氰基苄基衍生物（10a-c），用 6-叔丁基取代 4-硝基苄基衍生物（10j），发现其活性进一步提高。10a 的对映异构体的拆分表明，强 MDM2-p53 活性存在于（-）-对映异构体（（-）-10a；IC50=44±6 nM）中。关键化合物的细胞活性已在具有明确 p53 和 MDM2 状态的细胞系中进行了检测。化合物 10a 和（-）-10a 增加了 p53 蛋白水平，在 MDM2 扩增的细胞中激活了 p53 依赖性 MDM2 和 p21 转录，并在野生型 p53 细胞系中显示出比母体化合物更好的生长抑制选择性。
