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

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• 作者：Satoshi Takano ; Takayoshi Tsuzuki ; Takashi Murayama ; Takashi Sakurai ; Hayato Fukuda ; Mitsuhiro Arisawa ; Satoshi Shuto
• 刊名：Journal of Organic Chemistry
• 出版年：2015
• 出版时间：July 2, 2015
• 年：2015
• 卷：80
• 期：13
• 页码：6619-6627
• 全文大小：517K
• ISSN：1520-6904

文摘

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.