Synthesis, antiproliferative activity and molecular docking studies of neo- and isocryptolepine conjugates

IF 2.2 4区 化学 Q3 CHEMISTRY, MULTIDISCIPLINARY Journal of the Iranian Chemical Society Pub Date : 2024-09-10 DOI:10.1007/s13738-024-03078-8
Kholoud Heshmat, Asmaa T. Mohamed, Samah A. Loutfy, Ramy Mohamed AbdElaziz, Mehrez E. El-Naggar, Mohamed A. Hamed, Mohamed Atef, Elbadawy A. Kamoun, Ibrahim El-Tantawy El-Sayed, Yasmine S. Moemen
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Abstract

A series of twelve conjugates 9a-c, 10a-c, 11a-c, and 12a-c based on naturally occurring neo- and isocryptolepines I and II were synthesized and characterized. The synthetic pathways involved nucleophilic substitution reaction of the preprepared amines 4a-c and 5a-c with 1-(4-bromobutyl)indole derivatives 8a and 8b, respectively, in aprotic solvent under heating. The structures of the synthesized conjugates were elucidated by FTIR, 1H NMR, 13C NMR, and MS spectrometry and showed data consistence with the expected structures. The antiproliferative activity of 9a-c, 10a-c, 11a-c and 12a-c was evaluated against HepG-2 and HCT-116 cancer cell lines using normal cells and reference drug paclitaxel. The screening results revealed that 9b and 9c were the most active conjugates against HepG-2 and HCT-116 cancer cell lines with IC50: 8.49, 9.52, 16.87, 21.75 µM, respectively, using paclitaxel as a reference drug. It is worth noting that 9b and 9c were more selective toward cancer cells versus normal Vero cells. To rationalize the anticancer activity and selectivity of 9b and 9c, we have performed molecular docking study against human topoisomerases I and II for better understanding of their anticancer activities in atomic level. Molecular docking studies revealed that the presence of planar indoloquinoline fused four rings and a flexible side chain pharmacophores together improve DNA-intercalation and inhibition of DNA-Topo isomerases activity.

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新鸦胆子碱和异鸦胆子碱共轭物的合成、抗增殖活性和分子对接研究
以天然新吲哚和异吲哚啉 I 和 II 为基础,合成了一系列共轭物 9a-c、10a-c、11a-c 和 12a-c,并对其进行了表征。合成过程包括在加热的非烷基溶剂中,将制备的胺 4a-c 和 5a-c 分别与 1-(4-溴丁基)吲哚衍生物 8a 和 8b 进行亲核取代反应。通过傅立叶变换红外光谱、1H NMR、13C NMR 和 MS 光谱分析阐明了合成共轭物的结构,结果表明数据与预期结构一致。利用正常细胞和参考药物紫杉醇评估了 9a-c、10a-c、11a-c 和 12a-c 对 HepG-2 和 HCT-116 癌细胞株的抗增殖活性。筛选结果表明,9b 和 9c 是对 HepG-2 和 HCT-116 癌细胞株最有效的共轭物,以紫杉醇为参照药物,其 IC50 分别为 8.49、9.52、16.87 和 21.75 µM。值得注意的是,与正常 Vero 细胞相比,9b 和 9c 对癌细胞的选择性更高。为了合理解释 9b 和 9c 的抗癌活性和选择性,我们针对人类拓扑异构酶 I 和 II 进行了分子对接研究,以更好地了解它们在原子水平上的抗癌活性。分子对接研究发现,平面吲哚喹啉融合四环和柔性侧链药噬体的存在共同提高了 DNA 介导和抑制 DNA 拓扑异构酶的活性。
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来源期刊
CiteScore
4.40
自引率
8.30%
发文量
230
审稿时长
5.6 months
期刊介绍: JICS is an international journal covering general fields of chemistry. JICS welcomes high quality original papers in English dealing with experimental, theoretical and applied research related to all branches of chemistry. These include the fields of analytical, inorganic, organic and physical chemistry as well as the chemical biology area. Review articles discussing specific areas of chemistry of current chemical or biological importance are also published. JICS ensures visibility of your research results to a worldwide audience in science. You are kindly invited to submit your manuscript to the Editor-in-Chief or Regional Editor. All contributions in the form of original papers or short communications will be peer reviewed and published free of charge after acceptance.
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