Synthesis of 7‑Deaza-cyclic Adenosine-5′-diphosphate-carbocyclic-ribose and Its 7‑Bromo Derivative as Intracellular Ca2+-Mobilizing Agents

Cyclic ADP-carbocyclic-ribose (cADPcR, 3) is a biologically and chemically stable equivalent of cyclic ADP-ribose (cADPR, 1), a Ca2+-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...

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Published inJournal 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
LanguageEnglish
Japanese
Published WASHINGTON American Chemical Society 03.07.2015
Amer Chemical Soc
Subjects
Chemistry
Chemistry, Organic
Physical Sciences
Science & Technology
2ND-MESSENGER
NORTHERN RIBOSE
CYCLIC-ADP-RIBOSE
CARBOCYCLIC-RIBOSE
ANALOGS
HYDROLYSIS
CALCIUM MOBILIZATION
CHEMICAL-SYNTHESIS
MEMBRANE-PERMEANT
CYCLIZATION
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Summary:Cyclic ADP-carbocyclic-ribose (cADPcR, 3) is a biologically and chemically stable equivalent of cyclic ADP-ribose (cADPR, 1), a Ca2+-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 Ca2+-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.
Bibliography:KAKEN
ISSN:0022-3263
1520-6904
DOI:10.1021/acs.joc.5b00723