Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara, 44121 Ferrara, Italy.
Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara, 44121 Ferrara, Italy.
Eur J Med Chem. 2017 Jul 7;134:258-270. doi: 10.1016/j.ejmech.2017.03.089. Epub 2017 Apr 13.
The 2-oxindole nucleus is the central core to develop new anticancer agents and its substitution at the 3-position can effect antitumor activity. Utilizing a pharmacophore hybridization approach, a novel series of antiproliferative agents was obtained by the modification of the structure of 3-substituted-2-oxindole pharmacophore by the attachment of the α-bromoacryloyl moiety, acting as a Michael acceptor, at the 5-position of 2-oxindole framework. The impact of the substituent at the 3-position of 2-oxindole core on the potency and selectivity against a panel of seven different cancer cell lines was examined. We found that these hybrid molecules displayed potent antiproliferative activity against a panel of four cancer cell lines, with one-to double digit nanomolar 50% inhibitory concentrations (IC). A distinctive selective antiproliferative activity was obtained towards CCRF-CEM and RS4; 11 leukemic cell lines. In order to study the possible mechanism of action, we observed that the two most active compounds namely 3(E) and 6(Z) strongly induce apoptosis that follow the mitochondrial pathway. Interestingly a decrease of intracellular reduced glutathione content (GSH) and reactive oxygen species (ROS) production was detected in treated cells compared with controls suggesting that these effects may be involved in their mechanism of action.
2-氧吲哚核是开发新型抗癌药物的核心，其 3 位取代基可以影响抗肿瘤活性。利用药效团杂交方法，通过在 2-氧吲哚骨架的 5 位连接α-溴丙烯酰基部分（作为迈克尔受体），对 3-取代 2-氧吲哚药效团的结构进行修饰，得到了一系列新型具有抗增殖活性的化合物。我们考察了 2-氧吲哚核心 3 位取代基对一组七种不同癌细胞系的效力和选择性的影响。我们发现，这些杂合分子对一组四种癌细胞系表现出很强的抗增殖活性，半数抑制浓度（IC）为纳摩尔级的 1 到 2 位数。对 CCRF-CEM 和 RS4；11 种白血病细胞系具有独特的选择性抗增殖活性。为了研究可能的作用机制，我们观察到两种最活跃的化合物 3(E)和 6(Z)强烈诱导细胞凋亡，遵循线粒体途径。有趣的是，与对照组相比，处理细胞中的还原型谷胱甘肽（GSH）和活性氧（ROS）含量降低，表明这些效应可能与其作用机制有关。
