Chemistry of Cyclic ADP-Ribose and its Analogs

Abstract

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.

CD38 Structure-Based Inhibitor Design Using the N1-Cyclic Inosine 5′-Diphosphate Ribose Template

“…cADPR is readily hydrolyzed at the unstable N 1 link to give ADP-ribose (ADPR) in both neutral aqueous solution and under physiological conditions [2]–[4], thus rendering chemical synthesis of non-hydrolyzable analogues attractive. In-depth reviews dealing with the chemistry of cADPR and the cADPR/Ca 2+ signaling system have been published in recent years [5]–[11].…”

Cellular effects and metabolic stability of N1‐cyclic inosine diphosphoribose and its derivatives

“…The role of cADPR as an important signal transducer in human cell types implies that analogues of the molecule may become relevant as therapeutical agents in the future. Accordingly, the biological activity and metabolical stability of a number of such analogues have been studied (reviewed by Guse, 2004b; Potter and Walseth, 2004; Shuto and Matsuda, 2004). Alterations in the adenine base resulted in metabolically stable analogues: 3‐deaza‐cADPR is a potent and hydrolysis‐resistant agonist (Wong et al ., 1999), whereas 7‐deaza‐cADPR is also resistant to hydrolysis, but only a partial agonist (Sethi et al ., 1997).…”

ADP-Ribosyl Cyclase as a Therapeutic Target for Central Nervous System Diseases

“…mimic, cADP-carbocyclic-ribose (cADPcR), was synthesized. This method has been applied subsequently to the synthesis of various cADPR analogs [164,100].…”