title: Synthesis of 7-Deaza-cyclic Adenosine-5'-diphosphate-carbocyclic-ribose and Its 7-Bromo Derivative as Intracellular Ca(2+)-Mobilizing Agents.
abstract: 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.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takano
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Tsuzuki
authors.affiliation: §Department of Pharmacology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Murayama
authors.affiliation: §Department of Pharmacology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Sakurai
authors.forename: Hayato
authors.initials: H
authors.lastname: Fukuda
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Arisawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shuto
mesh_terms: D000818:Animals; D001686:Biological Phenomena; D020013:Calcium Signaling / Q000187:drug effects*; D036563:Cyclic ADP-Ribose / Q000031:analogs & derivatives* / Q000737:chemistry; D012617:Sea Urchins; D013329:Structure-Activity Relationship; D014372:Tubercidin / Q000031:analogs & derivatives / Q000737:chemistry*
chemical_list: C106088:7-deaza cyclic adenosine 5'-diphosphate ribose; C439996:cyclic ADP-carbocyclic-ribose; D036563:Cyclic ADP-Ribose; D014372:Tubercidin