作为潜在 AKT 抑制剂的新型抗癌香豆素-三唑-珊瑚酮杂交化合物的合成

IF 0.4 4区 化学 Q4 CHEMISTRY, ORGANIC INDIAN JOURNAL OF CHEMISTRY Pub Date : 2023-11-17 DOI:10.56042/ijc.v62i11.2610
E. Mallikarjun, D. Suneesha, Niranjana Kumar, Akanksha Singh, Hashnu Dutta, Kotesh Kumar, V. N. Satya, A. Meena, B. Venkatesh, N. Jain, Sravanthi, T. Radhika
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摘要

这篇研究文章介绍了一系列新型香豆素-三唑-查耳酮杂环类似物的合成,它们是具有新型抗癌作用模式的潜在生物活性物质。这些化合物是通过醛醇缩合和 1,3-二极环加成法合成的,从而产生了结合两种或两种以上药性的杂环系统。合成的化合物在体外对多种人类癌细胞系进行了抗癌活性筛选,包括 A549(肺癌)、HeLa(宫颈癌)、PANC1(胰腺癌)、HT1080(纤维肉瘤)和 HEK293(人类胚胎肾细胞)。与其他化合物相比,其中一种化合物对位腈查尔酮 9a 显示出显著的 IC 50 值,范围在 3.1 至 7.02 µg/mL 之间。所有化合物 9a - d 对 HEK-293 细胞都显示出较高的 IC 50 值,表明它们对正常细胞无毒。此外,作者还采用了硅学方法来评估在 MTT 试验中对分子靶标有活性的化合物的功效。作者将胰腺癌、肺癌、宫颈癌和纤维肉瘤的常见靶标生物标志物 PI3K 和 AKT 蛋白与化合物 9a 和一些已知抑制剂进行了对接研究。结果表明,化合物 9a 与 AKT(-10.6)和 PI3K(-10.3)具有良好的结合亲和力。然而,由于其结合位点氨基酸相互作用与已知的 AKT 抑制剂相似,因此发现它对 AKT 的特异性更强。这些发现证明,杂环混合系统可能有助于开发具有新作用模式的潜在生物活性物质,用于抗癌治疗。
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Synthesis of Novel Anticancer Coumarin-Triazole-Chalcone Hybrids as Potential AKT Inhibitor
This research article presents the synthesis of a novel series of hybrid analogues of Coumarin-Triazole-Chalcone, which are potential bioactives with a novel mode of action for anticancer therapy. The compounds have been synthesized via aldol condensation and 1,3-dipolar cycloaddition, resulting in the generation of hybrid heterocyclic systems that combine two or more pharmacophores. The synthesized compounds have then been screened for anticancer activity against various human cancer cell lines, including A549 (lung cancer), HeLa (Cervix carcinoma), PANC1 (pancreatic cancer), HT1080 (Fibrosarcoma) and HEK293 (Human embryonic kidney cells), in vitro . One of the compounds, para -nitrile chalcone 9a , demonstrates significant IC 50 values in the range of 3.1 to 7.02 µg/mL when compared to the others. All the compounds 9a - d have shown higher IC 50 values towards HEK-293 cells indicating their non-toxic nature towards normal cells. Furthermore, in silico approaches have been employed to assess the efficacy of compounds that are active in the MTT assay against molecular targets. The authors conducted docking studies of the proteins PI3K and AKT, which are common target biomarkers in Pancreatic cancer, Lung cancer, Cervical cancer, and Fibrosarcoma, with compound 9a and some known inhibitors. The results show that compound 9a has a good binding affinity with AKT (–10.6) and PI3K (–10.3). However, it is found to be more specific for AKT as its binding site amino acid interactions are similar to those of known AKT inhibitors. These findings provide evidence that hybrid heterocyclic systems may be useful for developing potential bioactives with a novel mode of action for anticancer therapy.
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