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.

 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 -c 、 9和10a-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。