Department of Chemistry, Ludwig-Maximilians-Universität München, Butenandtstrasse 5-13, 81377, Munich, Germany.
Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Feodor-Lynen-Strasse 25, 81377, Munich, Germany.
Chemistry. 2019 Feb 6;25(8):2089-2095. doi: 10.1002/chem.201805409. Epub 2019 Jan 17.
2'3'-cGAMP is an uncanonical cyclic dinucleotide where one A and one G base are connected via a 3'-5' and a unique 2'-5' linkage. The molecule is produced by the cyclase cGAS in response to cytosolic DNA binding. cGAMP activates STING and hence one of the most powerful pathways of innate immunity. cGAMP analogues with uncharged linkages that feature better cellular penetrability are currently highly desired. Here, the synthesis of a cGAMP analogue with one amide and one triazole linkage is reported. The molecule is best prepared via a first Cu -catalyzed click reaction, which establishes the triazole, while the cyclization is achieved by macrolactamization.
2'3'-cGAMP 是一种非经典的环二核苷酸，其中一个 A 和一个 G 碱基通过 3'-5' 和独特的 2'-5' 键连接。该分子是由环化酶 cGAS 响应细胞溶质 DNA 结合而产生的。cGAMP 激活 STING，因此是先天免疫的最强大途径之一。目前非常需要具有非荷电键的 cGAMP 类似物，其具有更好的细胞通透性。在此，报道了一种具有一个酰胺和一个三唑键的 cGAMP 类似物的合成。该分子最好通过首次 Cu 催化的点击反应来制备，该反应建立了三唑，而环化则通过大环内酯化来实现。
