The Chemistry of the Noncanonical Cyclic Dinucleotide 2′3′-cGAMP and Its Analogs

Abstract

The cyclic dinucleotides (CDNs) cyclic diguanosine monophosphate (c-diGMP) and cyclic diadenosine monophosphate (c-diAMP) with two canonical 3′→5′ internucleotide linkages are ubiquitous second messenger molecules in bacteria, regulating a multitude of physiological processes. Recently the noncanonical CDN cyclic guanosine monophosphate-adenosine monophosphate (2′3′-cGAMP) featuring a mixed linkage, which consists of a 2′→5′ and a 3′→5′ internucleotide bond, has been identified as a signaling molecule in metazoan species in late 2012. 2′3′-cGAMP formation is biocatalyzed by cGAMP synthase (cGAS) upon sensing of cytosolic double-stranded DNA (dsDNA) and functions as an endogenous inducer of innate immunity by directly binding to and activating the adaptor protein stimulator of interferon genes (STING). Thereby 2′3′-cGAMP can stimulate interferon-β (INF-β) secretion, a major signaling pathway of host defense, which is independent of toll-like receptor (TLR) activation. Medicinal chemistry of 2′3′-cGAMP and development of corresponding analogs are still in their infancy, and only a handful of structurally related compounds are available to the scientific community. The aim of this chapter is to summarize synthetic approaches to prepare canonical and noncanonical endogenous CDNs including 2′3′-cGAMP. Furthermore, we will describe syntheses of 2′3′-cGAMP analogs bearing modifications, which will facilitate further studies of the emerging biological functions of 2′3′-cGAMP and to identify additional receptor proteins. Finally, we will review latest developments concerning 2′3′-cGAMP analogs with improved hydrolytic stability in cell cultures and in tissues, putatively qualifying for new therapeutic options on the basis of 2′3′-cGAMP signaling.