Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Bioorg Med Chem Lett. 2021 Jun 1;41:128008. doi: 10.1016/j.bmcl.2021.128008. Epub 2021 Apr 6.
Various 6-alkynyl analogues of a known 3-nitro-2-(trifluoromethyl)-2H-chromene antagonist 3 of the G-coupled P2Y receptor (P2YR) were synthesized using a Sonogashira reaction to replace a 6-iodo group. The analogues were tested in a functional assay consisting of inhibition of calcium mobilization in P2YR-expressing astrocytoma cells elicited by native P2YR agonist UDP. 6-Ethynyl and 6-cyano groups were installed, and the alkynes were extended through both alkyl and aryl spacers. The most potent antagonists, with IC of ~1 µM, were found to be trialkylsilyl-ethynyl 7 and 8 (3-5 fold greater affinity than reference 3), t-butyl prop-2-yn-1-ylcarbamate 14 and p-carboxyphenyl-ethynyl 16 derivatives, and 3 and 8 displayed surmountable antagonism of UDP-induced production of inositol phosphates. Other chain-extended terminal carboxylate derivatives were less potent than the corresponding methyl ester derivatives. Thus, the 6 position in this chromene series is suitable for derivatization with flexibility of substitution, even with sterically extended chains, without losing P2YR affinity. However, a 3-carboxylic acid or 3-ester substitution did not serve as a nitro bioisostere, as the affinity was eliminated. These compounds provide additional ligand tools for the underexplored P2YR, which is a target for inflammatory, neurodegenerative and metabolic diseases.
使用 Sonogashira 反应合成了已知 G 蛋白偶联 P2Y 受体 (P2YR) 的 3-硝基-2-(三氟甲基)-2H-色烯拮抗剂 3 的各种 6-炔基类似物，以取代 6-碘基团。将类似物在功能测定中进行了测试，该测定包括抑制 P2YR 表达的星形细胞瘤细胞中钙动员，由天然 P2YR 激动剂 UDP 引发。安装了 6-乙炔基和 6-氰基基团，并且通过烷基和芳基间隔基延伸了炔。最有效的拮抗剂，IC 约为 1µM，发现是三烷基甲硅烷基-乙炔基 7 和 8（比参考物 3 高 3-5 倍的亲和力），叔丁基丙炔-1-基氨基甲酸酯 14 和对羧基苯基-乙炔基 16 衍生物，并且 3 和 8 显示出对 UDP 诱导的肌醇磷酸产生的可叠加拮抗作用。其他链延伸的末端羧酸衍生物的效力低于相应的甲酯衍生物。因此，在该色烯系列中，6 位适合进行取代，即使取代链具有较大的空间位阻，也不会失去 P2YR 的亲和力。然而，3-羧酸或 3-酯取代不能作为硝基生物等排体，因为亲和力被消除了。这些化合物为研究较少的 P2YR 提供了额外的配体工具，P2YR 是炎症、神经退行性和代谢疾病的靶标。
