新型[(3-吲哚基亚甲基)肼基]吲哚啉-2-酮作为凋亡抗增殖剂：设计、合成及体外生物学评价
Novel [(3-indolylmethylene)hydrazono]indolin-2-ones as apoptotic anti-proliferative agents: design, synthesis and in vitro biological evaluation.
作者信息
Eldehna Wagdy M, Abo-Ashour Mahmoud F, Ibrahim Hany S, Al-Ansary Ghada H, Ghabbour Hazem A, Elaasser Mahmoud M, Ahmed Hanaa Y A, Safwat Nesreen A
机构信息
a Department of Pharmaceutical Chemistry, Faculty of Pharmacy , Kafrelsheikh University , Kafrelsheikh , Egypt.
b Department of Pharmaceutical Chemistry, Faculty of Pharmacy , Egyptian Russian University , Badr City , Egypt.
出版信息
J Enzyme Inhib Med Chem. 2018 Dec;33(1):686-700. doi: 10.1080/14756366.2017.1421181.
On account of their significance as apoptosis inducing agents, merging indole and 3-hydrazinoindolin-2-one scaffolds is a logic tactic for designing pro-apoptotic agents. Consequently, 27 hybrids (6a-r, 9a-f and 11a-c) were synthesised and evaluated for their cytotoxicity against MCF-7, HepG-2 and HCT-116 cancer cell lines. SAR studies unravelled that N-propylindole derivatives were the most active compounds such as 6n (MCF-7; IC=1.04 µM), which displayed a significant decrease of cell population in the G2/M phase and significant increase in the early and late apoptosis by 19-folds in Annexin-V-FTIC assay. Also, 6n increased the expression of caspase-3, caspase-9, cytochrome C and Bax and decreased the expression of Bcl-2. Moreover, compounds 6i, 6j, 6n and 6q generated ROS by significant increase in the level of SOD and depletion of the levels of CAT and GSH-Px in MCF-7.
鉴于吲哚和3-肼基吲哚啉-2-酮支架作为凋亡诱导剂的重要性，将它们融合是设计促凋亡剂的合理策略。因此，合成了27种杂合物（6a-r、9a-f和11a-c），并评估了它们对MCF-7、HepG-2和HCT-116癌细胞系的细胞毒性。构效关系研究表明，N-丙基吲哚衍生物是最具活性的化合物，如6n（MCF-7；IC=1.04 µM），在Annexin-V-FTIC检测中，其在G2/M期细胞数量显著减少，早期和晚期凋亡显著增加19倍。此外，6n增加了caspase-3、caspase-9、细胞色素C和Bax的表达，降低了Bcl-2的表达。此外，化合物6i、6j、6n和6q通过显著增加MCF-7中SOD水平以及消耗CAT和GSH-Px水平而产生活性氧。
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