Total Synthesis of Cyclic ADP-carbocyclic-ribose, a Stable Mimic of Ca²⁺-Mobilizing Second Messenger Cyclic ADP-Ribose¹

Abstract

The synthesis of cyclic ADP-carbocyclic-ribose (cADPcR, 4) designed as a stable mimic of cyclic ADP-ribose (cADPR, 1), a Ca2+-mobilizing second messenger, was achieved using as the key step a condensation reaction with the phenylthiophosphate-type substrate 14 to form an intramolecular pyrophosphate linkage. The N-1-carbocyclic-ribosyladenosine derivative 16 was prepared via the condensation between the imidazole nucleoside derivative 17, prepared from AICA-riboside (19), and the readily available optically active carbocyclic amine 18. Compound 16 was then converted to the corresponding 5' '-phosphoryl-5'-phenylthiophosphate derivatives 14. Treatment of 14 with AgNO3 in the presence of molecular sieves (3 A) in pyridine at room temperature gave the desired cyclization product 32 in 93% yield, and subsequent acidic treatment provided the target cADPcR (4). This represents a general method for synthesizing biologically important cyclic nucleotides of this type. 1H NMR analysis of cADPcR suggested that its conformation in aqueous medium is similar to that of cADPR. cADPcR, unlike cADPR, was stable under neutral and acidic conditions, where under basic conditions, it formed the Dimroth-rearranged N6-cyclized product 34. cADPcR was also stable in rat brain membrane homogenate which has cADPR degradation activity. Furthermore, cADPcR was resistant to the hydrolysis by CD38 cADPR hydrolase, while cADPR was rapidly hydrolyzed under the same conditions. When cADPcR was injected into sea urchin eggs, it caused a significant release of Ca2+ in the cells, an effect considerably stronger than that of cADPR. Thus, cADPcR was identified as a stable mimic of cADPR.

Roles and mechanisms of the CD38/cyclic adenosine diphosphate ribose/Ca2+signaling pathway

“…Later, Lee et al [5] solved the structure of cADPR by x-ray crystallography and showed that it is a novel cyclic nucleotide formed by the covalent linkage of the N1 nitrogen of the adenine ring to the anomeric carbon of the terminal ribose to become a closed cyclic structure (Figure 2). Benefiting from the identified structure, multiple cADPR analogs have been synthesized, which greatly promoted research on the role and mechanism of cADPR-mediated Ca 2+ signaling [6][7][8][9] . From the very beginning of research on cADPR, several pharmacological studies have clearly shown that the mechanism of cADPR-induced Ca 2+ release is different from that of IP3.…”

Pharmacological Modulation of Sarcoplasmic Reticulum Function in Smooth Muscle

“…However, new enzyme-independent methods Shuto et al, 2001) should allow for more analogs with structural diversity.…”

“…3-Deaza-cADPR differs from cADPR by the substitution of carbon for nitrogen at the purine ring 3-position (Wong et al, 1999). In cADPcR, the oxygen atom in the cADPR N-1-ribose ring is substituted by a methylene group (Fukuoka et al, 1999;Shuto et al, 2001). 2Ј A -DeoxycADPR has a deletion of the cADPR 2Ј-position hydroxyl group of the ribose moiety linked to the adenine, i.e., the adenosine ribose .…”

Cyclic ADP-Carbocyclic-Ribose and -4-Thioribose, as Stable Mimics of Cyclic ADP-Ribose, a Ca²⁺-Mobilizing Second Messenger

“…Acidic deprotection of 16 finally furnished cADPcR (2). 32) cADPcR was not only both chemically and biologically stable, but also effectively mobilizes intracellular Ca 2+ in sea urchin eggs 32) and is more potent than cADPR in neuronal cells. 33) In addition, cADPcR induced insulin secretion from digitonin-permeabilized rat islets via Ca 2+ -mobilization like as cADPR.…”