Chemistry of cyclic ADP-ribose and its analogs.
Cyclic ADP-ribose (cADPR), a general 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. This review focuses on the chemical synthetic studies of cADPR analogs. These analogs have been used quite effectively in proving the mechanism of cADPR-mediated Ca2+ signaling pathways. These analogs are also expected to be lead structures for the development of drugs. Although cADPR analogs can be synthesized by enzymatic and chemo-enzymatic methods using ADP-ribosyl cyclase, the analogs obtained by these methods are limited due to the substrate-specificity of the enzymes. Consequently, chemical synthetic methods providing a greater variety of cADPR analogs are required. Chemical synthetic studies have demonstrated that the construction of the large 18-membered ring structure is quite difficult. Another problem encountered in the synthesis is the construction of the N1-substituted purine nucleoside structure. The N1-substituted inosine derivatives were prepared by condensation between the N1-(2,4-dinitrophenyl)inosine derivatives and the appropriate amines. For the preparation of the N1-substituted adenosine structures, condensation of the 4-cyano-5-(alkoxymethyleneamino)imidazole nucleosides with the appropriate amines was found to be effective. The first chemical construction of the 18-membered ring was achieved using a bisphosphate-type substrate conformationally restricted in the cyclized product-like syn-form around the N9-glycosyl linkage; however, the yield was inadequate. The key 18-membereding construction was significantly improved by employing the phenylthiophosphate-type substrates. When the substrates were activated by AgNO3 or I2 in the presence of molecular sieves in pyridine, the corresponding 18-membered ring products were obtained in high yields. Using this method as the key step, the chemically and biologically stable cADPR mimic, cADP-carbocyclic-ribose (cADPcR), was synthesized. This method has been applied subsequently to the synthesis of various cADPR analogs.
Shuto
Satoshi
S
Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan. shu@pharm.hokudai.ac.jp
Matsuda
Akira
A
D036541:ADP-ribosyl Cyclase / Q000737:chemistry; D000818:Animals; D002118:Calcium / Q000378:metabolism; D036563:Cyclic ADP-Ribose / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry*; D015394:Molecular Structure; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D013329:Structure-Activity Relationship
C439996:cyclic ADP-carbocyclic-ribose; D036563:Cyclic ADP-Ribose; D036541:ADP-ribosyl Cyclase; D002118:Calcium