Synthesis of stable and cell-type selective analogues of cyclic ADP-ribose, a Ca2+-mobilizing second messenger.: Structure-activity relationship of the N1-ribose moiety
Synthesis of stable and cell-type selective analogues of cyclic ADP-ribose, a Ca2+-mobilizing second messenger.: Structure-activity relationship of the N1-ribose moiety
复制标题
DOI：
10.1021/ja050732x
复制
发表时间：
2005-06-22
影响因子：
15
通讯作者：
Shuto, S
中科院分区：
文献类型：
--
作者：
Kudoh, T;Fukuoka, M;Shuto, S
我们以前开发了环状ADP-碳环核糖（cADPcR，2）作为环状ADP-核糖（cADPR，1）的稳定模拟物，cADPR，1是Ca 2+动员的第二信使。设计了一系列N1 -核糖修饰的cADPcR类似物，作为cADPR的新型稳定模拟物，它们是2”-脱氧类似物3、3”-脱氧类似物4、3”-脱氧-2”- O-（甲氧基甲基）类似物5、3”-0-甲基类似物6、2”，3”-双脱氧类似物7和2”，3”-双脱氧双脱氧类似物8，成功地合成了使用关键的分子内缩合反应与苯硫代磷酸酯型底物。我们研究了这些类似物和cADFR的构象，发现腺嘌呤和N9-核糖部分之间以及腺嘌呤和N1-核糖部分之间的空间排斥是构象的决定因素。使用三种不同的生物系统，即，海胆卵、NG 108 -15神经元细胞和Jurkat T淋巴细胞。这些cADPR类似物的Ca 2+动员的相对效力取决于所用的细胞类型而变化：例如，在海胆卵中，cADPcR（4）> cADPcR（2）> cADPR（1）;在T细胞中，cADPcR（1）>> cADPcR（2）接近于3”-deoxy-cADPcR（4）;在神经细胞中，cADPcR（2）> cADPR（1）> 3”-deoxy-cADPcR（4）。这表明cADPR在海胆卵、T细胞和神经细胞中的靶蛋白和/或作用机制是不同的。因此，这项研究代表了进入细胞类型选择性cADPR类似物，可用作生物工具和/或新的药物线索。
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 cADFR 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 Ca2+ -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 Ca2+-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)approximate to 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.