5-Amino-7-Oxo-4,7-Dihydroazolo[1,5-a]pyrimidine-6-Carbonitriles: Synthesis and Study of Antitumor Effect In Vitro and In Silico.

IF 3.4 4区 医学 Q2 CHEMISTRY, MEDICINAL
ChemMedChem Pub Date : 2025-09-21 DOI:10.1002/cmdc.202500535
Veronika V Dolgova, Konstantin V Savateev, Grigoriy V Urakov, Evgeniya T Shabunina, Tatiana E Sbrodova, Ekaterina A Lvova, Ilya I Butorin, Elena A Fesenko, Vsevolod V Melekhin, Maria D Tokhtueva, Anastasiya V Paramonova, Andrey A Zonov, Svetlana K Kotovskaya, Vladimir L Rusinov
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引用次数: 0

Abstract

A novel chemotype of nitrile-containing azolopyrimidines with potential antitumor activity has been proposed, and a method for the synthesis of the corresponding 5-amino-7-oxoazolo[1,5-a]pyrimidine-6-carbonitriles by cyclocondensation of various aminoazoles and ethyl 2-cyano-3-R-amino-3-(methylsulfanyl)acrylates has been developed. Cytotoxic effects of the obtained azolopyrimidines against glioblastoma (A-172), bladder carcinoma (T-24), lung carcinoma (A-549), and human embryonic kidney (HEK-293) cells have been investigated, and structure-activity relationships have been identified. 2-Phenyl-5-(morpholin-4-yl)-7-oxo-1,2,4-triazolo[1,5-a]pyrimidine-6-carbonitrile 5j has been found to exhibit selective cytotoxic activity against the T-24 cells (IC50 = 14.68 µM), whereas 3-bromo-5-(morpholin-4-yl)-7-oxopyrazolo[1,5-a]pyrimidine-6-carbonitrile 5v has shown selective toxicity against the A-172 cells (IC50 = 18.38 µM). Further studies on heterocycle 5j in the annexin V apoptosis assay indicate that the primary mechanism involves inhibition of proliferative activity rather than induction of cell death. The cyclin-dependent kinase 2 protein is suggested as a possible target for the cytotoxic action of the studied compounds 5 on the T-24 cell line according to the notable correlation between docking studies and MTT assay results.

5-氨基-7-氧-4,7-二氢偶氮[1,5-a]嘧啶-6-碳腈的合成及体外和硅内抗肿瘤作用研究
提出了一种具有潜在抗肿瘤活性的含硝基氮唑嘧啶的新化学型,并开发了一种通过各种氨基唑和2-氰基-3- r -氨基-3-(甲基磺胺基)丙烯酸酯的环缩合反应合成相应的5-氨基-7-氧唑[1,5- A]嘧啶-6-碳腈的方法。研究了所获得的偶氮嘧啶对胶质母细胞瘤(A-172)、膀胱癌(T-24)、肺癌(A-549)和人胚胎肾(HEK-293)细胞的细胞毒作用,并确定了构效关系。2-苯基-5-(morpholin-4-yl)-7-氧-1,2,4-三氮唑[1,5-a]嘧啶-6-碳腈5j对T-24细胞具有选择性细胞毒性(IC50 = 14.68µM),而3-溴-5-(morpholin-4-yl)-7-氧吡唑[1,5-a]嘧啶-6-碳腈5v对A-172细胞具有选择性毒性(IC50 = 18.38µM)。在膜联蛋白V凋亡实验中对杂环5j的进一步研究表明,其主要机制是抑制增殖活性,而不是诱导细胞死亡。根据对接研究和MTT实验结果之间的显著相关性,周期蛋白依赖性激酶2蛋白被认为是所研究化合物5对T-24细胞系细胞毒性作用的可能靶点。
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来源期刊
ChemMedChem
ChemMedChem 医学-药学
CiteScore
6.70
自引率
2.90%
发文量
280
审稿时长
1 months
期刊介绍: Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies. ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs. Contents ChemMedChem publishes an attractive mixture of: Full Papers and Communications Reviews and Minireviews Patent Reviews Highlights and Concepts Book and Multimedia Reviews.
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