Synthesis of Stable and Cell-type Selective Analogues of Cyclic ADP-Ribose,a Ca~(2+)-Mobilizing Second Messenger.Structure- Activity Relationship of the N1-Ribose Moiety

摘要

We previously developed cyclic ADP-carbocyclic ribose (cADPcR,2) as a stable mimic of cyclic ADP-ribose (cADPR,1),a Ca2+-mobilizing second messenger.A series of the N1-ribose modified cADPcR analogues,designed as novel stable mimics of cADPR,which were the 2"-deoxy analogue 3,the 3"-deoxy analogue 4,the 3"-deoxy-2"-O-(methoxymethyl) analogue 5,the 3"-O-methyl analogue 6,the 2",3"-dideoxy analogue 7,and the 2",3"-dideoxydidehydro analogue 8,were successfully synthesized using the key intramolecular condensation reaction with phenylthiophosphate-type substrates.We investigated the conformations of these analogues and of cADPR and found that steric repulsion between both the adenine and N9-ribose moieties and between the adenine and N1-ribose moieties was a determinant of the conformation.The Ca~(2+)-mobilizing effects were evaluated systematically using three different biological systems,i.e.,sea urchin eggs,NG108-15 neuronal cells,and Jurkat T-lymphocytes.The relative potency of Ca~(2+)-mobilization by these cADPR analogues varies depending on the cell-type used:e.g.,3"-deoxy-cADPcR (4) > cADPcR (2) > cADPR (1) in sea urchin eggs;cADPR (1) cADPcR (2) approx= 3"-deoxy-cADPcR (4) in T-cells;and cADPcR (2) > cADPR (1) > 3"-deoxy-cADPcR (4) in neuronal cells,respectively.These indicated that the target proteins and/or the mechanism of action of cADPR in sea urchin eggs,T-cells,and neuronal cells are different.Thus,this study represents an entry to cell-type selective cADPR analogues,which can be used as biological tools and/or novel drug leads.