Chemistry of Cyclic Dinucleotides and Analogs

Cyclic dinucleotides (CDNs) are a class of macrocyclic natural product consisting of two nucleotides linked via two phosphodiester linkages. For example, a CDN composed of two guanine bases is called cyclic-di-GMP (c-di-GMP). CDNs are biosynthesized from two nucleoside 5′-triphosphates by cyclase enzymes, such as guanylate cyclase which synthesizes c-di-GMP. Since the 1980s, as the biological significance of CDNs has become clear, chemists have focused on the chemical synthesis of CDNs and analogs. These efforts have contributed significantly to the elucidation of the diverse biological process regulated by CDNs. This chapter addresses the chemistry of CDNs and analogs. In the first half of this chapter, synthetic strategies for making CDNs are outlined. The strategies are classified according to the key reactions which form the internal phosphodiester linkages and construct the CDN skeleton, namely dimerization and cyclization. In the second half of the report, chemically modified CDN analogs developed using the above chemistry are introduced.