title: 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.
authors.affiliation: BIOLOG Life Science Institute, Forschungslabor und Biochemica-Vertrieb GmbH, Flughafendamm 9a, 28199, Bremen, Germany. fs@biolog.de.
authors.forename: Frank
authors.initials: F
authors.lastname: Schwede
authors.affiliation: BIOLOG Life Science Institute, Forschungslabor und Biochemica-Vertrieb GmbH, Flughafendamm 9a, 28199, Bremen, Germany.
authors.forename: Hans-Gottfried
authors.initials: HG
authors.lastname: Genieser
authors.affiliation: BIOLOG Life Science Institute, Forschungslabor und Biochemica-Vertrieb GmbH, Flughafendamm 9a, 28199, Bremen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Rentsch
mesh_terms: D000818:Animals; D004355:Drug Stability; D006801:Humans; D006868:Hydrolysis; D015394:Molecular Structure; D009712:Nucleotides, Cyclic / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D015290:Second Messenger Systems / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D009712:Nucleotides, Cyclic; C584311:cyclic guanosine monophosphate-adenosine monophosphate
keywords: 2′3′-cGAMP; CDN; Chemical cGAMP analogs; Rp,Rp-2′3′-c-diAMPSS; STING; c-diGMP; cGAMP; cGAS