Nucleosides and Nucleotides. 173. Synthesis of Cyclic IDP-carbocyclic-ribose, a Stable Mimic of Cyclic ADP-ribose. Significant Facilitation of the Intramolecular Condensation Reaction of N-1-(Carbocyclic-ribosyl)inosine 5‘,6‘‘-Diphosphate Derivatives by an 8-Bromo-Substitution at the Hypoxanthine Moiety

Abstract

Cyclic ADP-ribose (cADPR, 1) is a general mediator involved in cellular Ca2+ signaling. However, both the biological and chemical instability of cADPR limit studies on its physiological role. We designed cyclic ADP-carbocyclic-ribose (3) and its inosine congener 4 as stable mimics of cADPR and successfully synthesized 4. Starting with cyclopentadiene, the optically active carbocyclic unit 8 was constructed via enzymatic optical resolution. SN2 reactions of 8 with inosine derivative 7 and the 8-bromoinosine derivative 25 gave the N-1-substituted derivatives 6 and 26, which were converted to the corresponding diphosphate derivatives 5 and 22. The intramolecular condensation reactions between the two phosphate groups of 5 and 22 were investigated. Although the reaction with inosine derivative 5 did not produce any of the cyclization product 20, treatment of the corresponding 8-bromoinosine derivative 22 with EDC gave the desired intramolecular condensation product 29 in 23% yield. Thus, the significant effec...