Design, synthesis, and biological activity of carbocyclic analogues of cyclic ADP-ribose, a Ca2+-mobilizing second messenger.

An efficient method for the total synthesis of cyclic ADP-ribose (cADPR, 1) analogues was established. In this procedure, formation of the characteristic 18membered ring was key step, which was achieved by the AgNO3-or I2-promoted condensation with the phenylthiophosphate-type substrate forming an intramolecular pyrophosphate linkage. Using this method, a variety of carbocyclic analogues of cADPR have been synthesized to investigate the structure-activity-relationship, where cyclic ADP-carbocyclic-ribose (2) was identified as a stable and cell-type selective cADPR agonist.