Conformational restriction of cyclic dinucleotides with triazole-linked cyclophane analogues

Cyclic dinucleotides (CDN) such as c-di-GMP and c-di-AMP are important multi-functional compounds that regulate a diverse range of processes in bacteria. The diversity of the functions is enabled by the two distinct conformations, that is, open and close conformations. We herein report the concise synthesis of triazole-linked analogues (c-di-GMPTL, c-di-AMPTL) through click dimerization of nucleoside analogues. The implementation of a cyclophane system in the central macrocycle furnished the structure with the conformational restriction to maintain the structure similar to the open conformer of natural congeners.