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