Department of Chemical and Pharmaceutical Sciences, University of Trieste, Via Licio Giorgieri 1, 34127, Trieste, Italy.
Department of Life Sciences, University of Trieste, Via Licio Giorgieri 5, 34127, Trieste, Italy.
ChemMedChem. 2023 Nov 2;18(21):e202300299. doi: 10.1002/cmdc.202300299. Epub 2023 Sep 22.
The A adenosine receptor is an interesting target whose role in cancer is controversial. In this work, a structural investigation at the 2-position of the [1,2,4]triazolo[1,5-c]pyrimidine nucleus was performed, finding new potent and selective A adenosine receptor antagonists such as the ethyl 2-(4-methoxyphenyl)-5-(methylamino)-[1,2,4]triazolo[1,5-c]pyrimidine-8-carboxylate (20, DZ123) that showed a K value of 0.47 nM and an exceptional selectivity profile over the other adenosine receptor subtypes. Computational studies were performed to rationalize the affinity and the selectivity profile of the tested compounds at the A adenosine receptor and the A and A adenosine receptors. Compound 20 was tested on both A adenosine receptor positive cell lines (CHO-A AR transfected, THP1 and HCT16) and on A negative cancer cell lines, showing no effect in the latter and a pro-proliferative effect at a low concentration in the former. These interesting results pave the way to further investigation on both the mechanism involved and potential therapeutic applications.
A 腺苷受体是一个有趣的靶点，其在癌症中的作用存在争议。在这项工作中，我们对[1,2,4]三唑并[1,5-c]嘧啶核的 2-位进行了结构研究，发现了新的强效和选择性 A 腺苷受体拮抗剂，如乙基 2-(4-甲氧基苯基)-5-(甲氨基)-[1,2,4]三唑并[1,5-c]嘧啶-8-羧酸酯（20，DZ123），其 K 值为 0.47 nM，对其他腺苷受体亚型具有出色的选择性。还进行了计算研究，以合理地解释在 A 腺苷受体和 A 和 A 腺苷受体上测试化合物的亲和力和选择性。化合物 20 在 A 腺苷受体阳性细胞系（转染的 CHO-A AR、THP1 和 HCT16）和 A 阴性癌细胞系上进行了测试，在后者中没有作用，而在前者中以低浓度显示出促增殖作用。这些有趣的结果为进一步研究所涉及的机制和潜在的治疗应用铺平了道路。
