Synthesis of 7-Deaza-cyclic Adenosine-5'-diphosphate-carbocyclic-ribose and Its 7-Bromo Derivative as Intracellular Ca(2+)-Mobilizing Agents

• Published in: Journal of organic chemistry Vol. 80; no. 13; pp. 6619 - 6627
• Main Authors: Takano, Satoshi, Tsuzuki, Takayoshi, Murayama, Takashi, Sakurai, Takashi, Fukuda, Hayato, Arisawa, Mitsuhiro, Shuto, Satoshi
• Format: Journal Article
• Language: English
• Published: United States 02.07.2015
• Subjects: Animals; Biological Phenomena; Calcium Signaling - drug effects; Cyclic ADP-Ribose - analogs & derivatives; Cyclic ADP-Ribose - chemistry; Sea Urchins; Structure-Activity Relationship; Tubercidin - analogs & derivatives; Tubercidin - chemistry
• ISSN: 1520-6904
• DOI: 10.1021/acs.joc.5b00723

Cyclic ADP-carbocyclic-ribose (cADPcR, 3) is a biologically and chemically stable equivalent of cyclic ADP-ribose (cADPR, 1), a Ca(2+)-mobilizing second messenger. We became interested in the biological activity of the 7-deaza analogues of cADPcR, i.e., 7-deaza-cADPcR (7) and its 7-bromo derivative, i.e., 7-deaza-7-Br-cADPcR (8), because 7-deazaadenosine is an efficient bioisostere of adenosine. The synthesis of 7 and 8 required us to construct the key N1-carbocyclic-ribosyl-7-deazaadenosine structure. Therefore, we developed a general method for preparing N1-substituted 7-deazaadenosines by condensing a 2,3-disubstituted pyrrole nucleoside with amines. Using this method, we prepared the N1-carbocyclic ribosyl 7-deazaadenosine derivative 10a, from which we then synthesized the target 7-deaza-cADPcR (7) via an Ag(+)-promoted intramolecular condensation to construct the 18-membered pyrophosphate ring structure. The corresponding 7-bromo derivative 8, which was the first analogue of cADPR with a substitution at the 7-position, was similarly synthesized. Biological evaluation for Ca(2+)-mobilizing activity in the sea urchin egg homogenate system indicated that 7-deaza-cADPcR (7) and 7-deaza-7-Br-cADPcR (8) acted as a full agonist and a partial agonist, respectively.