Synthesis of Stable and Cell-type Selective Analogues of Cyclic ADP-Ribose, a Ca2+-Mobilizing Second Messenger. Structure-Activity Relationship of the N1-Ribose Moiety1

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• 作者：Takashi Kudoh ; Masayoshi Fukuoka ; Satoshi Ichikawa ; Takashi Murayama ; Yasuo Ogawa ; Minako Hashii ; Haruhiro Higashida ; Svenja Kunerth ; Karin Weber ; Andreas H. Guse ; Barry V. L. Potter ; Akira Matsuda ; a
• 刊名：Journal of the American Chemical Society
• 出版年：2005
• 出版时间：June 22, 2005
• 年：2005
• 卷：127
• 期：24
• 页码：8846 - 8855
• 全文大小：437K
• 年卷期：v.127,no.24(June 22, 2005)
• ISSN：1520-5126

文摘

We previously developed cyclic ADP-carbocyclic ribose (cADPcR, 2) as a stable mimic of cyclicADP-ribose (cADPR, 1), a Ca²⁺-mobilizing second messenger. A series of the N1-ribose modified cADPcRanalogues, designed as novel stable mimics of cADPR, which were the 2' '-deoxy analogue 3, the3' '-deoxy analogue 4, the 3' '-deoxy-2' '-O-(methoxymethyl) analogue 5, the 3' '-O-methyl analogue 6, the2' ',3' '-dideoxy analogue 7, and the 2' ',3' '-dideoxydidehydro analogue 8, were successfully synthesizedusing the key intramolecular condensation reaction with phenylthiophosphate-type substrates. Weinvestigated the conformations of these analogues and of cADPR and found that steric repulsion betweenboth the adenine and N9-ribose moieties and between the adenine and N1-ribose moieties was adeterminant of the conformation. The Ca²⁺-mobilizing effects were evaluated systematically using threedifferent biological systems, i.e., sea urchin eggs, NG108-15 neuronal cells, and Jurkat T-lymphocytes.The relative potency of Ca²⁺-mobilization by these cADPR analogues varies depending on the cell-typeused: e.g., 3' '-deoxy-cADPcR (4) > cADPcR (2) > cADPR (1) in sea urchin eggs; cADPR (1) cADPcR(2) 3' '-deoxy-cADPcR (4) in T-cells; and cADPcR (2) > cADPR (1) > 3' '-deoxy-cADPcR (4) in neuronalcells, respectively. These indicated that the target proteins and/or the mechanism of action of cADPR insea urchin eggs, T-cells, and neuronal cells are different. Thus, this study represents an entry to cell-typeselective cADPR analogues, which can be used as biological tools and/or novel drug leads.