作为癌症化学预防中脱氧核苷激酶类似物抑制剂的氨基嘧啶的同源性建模、分子对接研究和合成。

IF 1.1 4区 生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY
Jainey P James, Mariyam Jouhara B M, Sneh Priya, Divya Jyothi, Rajalakshimi Vasudevan
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引用次数: 0

摘要

由于哺乳动物恶性肿瘤复发率的上升和化疗的严重副作用,开发副作用最小的替代抗癌药物变得越来越重要。激酶在调节生长因子信号传导方面发挥着重要作用,因此是对新生物产生影响的重要靶点。我们的工作旨在通过分子对接、合成和体外抑制研究,筛选出针对线粒体胸苷激酶 2、脱氧鸟苷激酶(2OCP)、脱氧胞苷激酶(2QRN)和胸苷酸激酶(1E2Q)的九个系列的新型噻唑基氨基嘧啶和磺胺嘧啶。合成的化合物通过红外光谱、核磁共振和质谱进行了表征。在硅学研究中,化合物 4c 在系列化合物中脱颖而出,据报告其对所有类似激酶的对接得分在 -6 至 -8 Kcal/mol 之间。针对人小细胞肺癌(A-549)的体外细胞毒性试验表明,5c(IC50=53.9 µM)的细胞毒性效果优于 4c(IC50=68.68 µM)。原因可能是苯磺酰胺基团的存在增强了它们的抗癌作用。总之,研究发现化合物 4c 和 5c 是脱氧核苷激酶的强效抑制剂。体内研究必须进一步验证这些化合物,以证明它们具有强大的抗肿瘤作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Homology modelling, molecular docking studies and synthesis of aminopyrimidines as inhibitors for deoxynucleoside kinase analogues in cancer chemoprevention.

The development of alternative anticancer agents with minimal side effects has become more critical due to the rising recurrence of mammalian malignancies and the severe side effects of chemotherapeutic treatments. Kinases are an essential target for neostatic impact as they play an important role in the modulation of growth factor signalling. Our work aims to screen novel nine-series of thiazole-based aminopyrimidines and sulphaminopyrimidines against the enzymes mitochondrial thymidine kinase 2, deoxyguanosine kinase (2OCP), deoxycytidine kinase (2QRN) and thymidylate kinase (1E2Q) by molecular docking, synthesise and to study their in vitro inhibitory studies. The synthesised compounds were characterised by Infrared, Nuclear magnetic resonance and Mass spectroscopy. In silico studies, compound 4c stands out among the series, with a reported docking score ranging from -6 to -8 Kcal/mol against all the analogue kinases. The in vitro cytotoxicity assay against human small-cell lung carcinoma (A-549) has shown that 5c (IC50 = 53.9 µM) has an excellent cytotoxic effect over 4c (IC50= 68.68 µM). The reason might be the presence of the benzene sulphonamide group, which enhances their anticancer action. To conclude, the compounds 4c and 5c were found to be potent inhibitors of the deoxynucleoside kinases. In vivo studies must further verify these to prove their potent neostatic effect.

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来源期刊
Nucleosides, Nucleotides & Nucleic Acids
Nucleosides, Nucleotides & Nucleic Acids 生物-生化与分子生物学
CiteScore
2.60
自引率
7.70%
发文量
91
审稿时长
6 months
期刊介绍: Nucleosides, Nucleotides & Nucleic Acids publishes research articles, short notices, and concise, critical reviews of related topics that focus on the chemistry and biology of nucleosides, nucleotides, and nucleic acids. Complete with experimental details, this all-inclusive journal emphasizes the synthesis, biological activities, new and improved synthetic methods, and significant observations related to new compounds.
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