Abstract
Cyclic ADP-ribose (cADPR), a mediator involved in Ca2+ signaling, has the characteristic 18-membered ring consisting of an adenine, two riboses and a pyrophosphate, in which the two primary hydroxyl groups of the riboses are linked by a pyrophosphate unit. The analogues of cADPR can be used quite effectively in proving the mechanism of cADPR-mediated Ca2+ signaling pathways. These analogues are also expected to be lead structures for the development of drugs. Therefore, A variety of cADPR analogues modified in the base, sugars, and pyrophosphate moieties have been designed and synthesized. We designed cyclic ADP-carbocyclic-ribose (cADPcR), in which the ring oxygen in the "northern" ribose is replaced by a methylene unit. Since they lack the unstable N1-ribosyl linkage of cADPR, this carbocyclic analogue should be resistant to both enzymatic and chemical hydrolysis, while still preserving most of the functional groups of cADPR. We first developed an efficient chemical total synthetic method for cADPR analogues to accomplish the synthesis of cADPcR. Biological evaluations of cADPcR showed that cADPcR actually functions as a stable mimic of cADPR.The structure-activity relationship of cADPR analogues including cADPcR will be discussed. [Jpn J Physiol 54 Suppl:S17 (2004)]
