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Novel [(N-alkyl-3-indolylmethylene)hydrazono]oxindoles arrest cell cycle and induce cell apoptosis by inhibiting CDK2 and Bcl-2: synthesis, biological evaluation and in silico studies.
Journal of Enzyme inhibition and Medicinal Chemistry ( IF 5.6 ) Pub Date : 2020-06-11 , DOI: 10.1080/14756366.2020.1773814
Tarfah Al-Warhi 1 , Mahmoud F Abo-Ashour 2 , Hadia Almahli 3 , Ohoud J Alotaibi 1 , Mohammad M Al-Sanea 4 , Ghada H Al-Ansary 5, 6 , Hanaa Y Ahmed 7 , Mahmoud M Elaasser 7 , Wagdy M Eldehna 8 , Hatem A Abdel-Aziz 9
Affiliation  

Abstract

As a continuation for our previous work, a novel set of N-alkylindole-isatin conjugates (7, 8a–c, 9 and 10a–e) is here designed and synthesised with the prime aim to develop more efficient isatin-based antitumor candidates. Utilising the SAR outputs from the previous study, our design here is based on appending four alkyl groups with different length (ethyl and n-propyl), bulkiness (iso-propyl) and unsaturation (allyl) on N-1 of indole motif, with subsequent conjugation with different N-unsubstituted isatin moieties to furnish the target conjugates. As planned, the adopted strategy achieved a substantial improvement in the growth inhibitory profile for the target conjugates in comparison to the reported lead VI. The best results were obtained with N-propylindole –5-methylisatin hybrid 8a which displayed broad spectrum anti-proliferative action with efficient sub-panel GI50 (MG-MID) range from 1.33 to 4.23 µM, and promising full-panel GI50 (MG-MID) equals 3.10 µM, at the NCI five-dose assay. Also, hybrid 8a was able to provoke cell cycle disturbance and apoptosis in breast T-47D cells as evidenced by the DNA flow cytometry and Annexin V-FITC/PI assays. Furthermore, hybrid 8a exhibited good inhibitory action against cell cycle regulator CDK2 protein kinase and the anti-apoptotic Bcl-2 protein (IC50= 0.85 ± 0.03 and 0.46 ± 0.02 µM, respectively). Interestingly, molecular docking for hybrid 8a in CDK2 and Bcl-2 active sites unveiled that N-propyl group is involved in significant hydrophobic interactions. Taken together, the results suggested conjugate 8a as a promising lead for further development and optimisation as an efficient antitumor drug.



中文翻译:


新型[(N-烷基-3-吲哚亚甲基)亚肼基]oxindoles 通过抑制 CDK2 和 Bcl-2 来阻止细胞周期并诱导细胞凋亡:合成、生物学评价和计算机研究。


 抽象的


作为我们之前工作的延续,本文设计并合成了一组新型N-烷基吲哚-靛红缀合物( 7、8a -c910a-e ),主要目的是开发更有效的基于靛红的抗肿瘤候选药物。利用之前研究的 SAR 输出,我们的设计基于在吲哚基序的N -1 上附加四个不同长度(乙基和正丙基)、体积(异丙基)和不饱和度(烯丙基)的烷基,随后与不同的N-未取代的靛红部分缀合以提供目标缀合物。按照计划,与报道的先导VI相比,所采用的策略显着改善了目标缀合物的生长抑制特性。 N-丙基吲哚 –5-甲基靛红杂化物8a获得了最佳结果,它显示出广谱抗增殖作用,有效的亚组 GI 50 (MG-MID) 范围为 1.33 至 4.23 µM,并且有前景的全组 GI 50 (在 NCI 五剂量测定中,MG-MID)等于 3.10 µM。此外,DNA 流式细胞术和膜联蛋白 V-FITC/PI 测定证明,Hybrid 8a能够引起乳腺 T-47D 细胞的细胞周期紊乱和细胞凋亡。此外,hybrid 8a对细胞周期调节剂 CDK2 蛋白激酶和抗凋亡 Bcl-2 蛋白表现出良好的抑制作用(IC 50分别为 0.85 ± 0.03 和 0.46 ± 0.02 µM)。有趣的是,CDK2 和 Bcl-2 活性位点中杂合体8a的分子对接揭示了N-丙基参与了显着的疏水相互作用。 综上所述,结果表明缀合物8a是进一步开发和优化作为有效抗肿瘤药物的有希望的先导化合物。

更新日期:2020-06-11
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