Synthesis of Novel 3’,3’‐cyclic Dinucleotide Analogues Targeting STING Protein

The Stimulator of Interferon Genes (STING) plays an important role in innate immunity by inducing type I interferons in response to sensing viral or bacterial cytosolic DNA. Cyclic dinucleotides (CDNs) are known to activate STING. Here, we describe the synthesis and biological evaluation of two new 3’,3’‐CDN, in which the internucleotide linkages were replaced, respectively, by a 1,2,3‐triazole moiety (as more stable isosteres of phosphate linkers) and an unsaturated carbon chain (as flexibility can led to crucial binding affinity and specificity). Thus, CuAAC and macrocyclization by RCM are the two key steps. Starting from chiral sugars, new cyclic dinucleotides are described; the synthesis involves (1) the coupling of both sugar moieties through CuAAC reaction, (2) the macrocyclization of resulting intermediate under ring‐closing metathesis and (3) the introduction of nucleobases by N‐glycosylation under Vorbrüggen conditions. These compounds are targeting the STING protein.