Total synthesis of cyclic ADP-carbocyclic-ribose, a stable mimic of Ca2+-mobilizing second messenger cyclic ADP-ribose
Total synthesis of cyclic ADP-carbocyclic-ribose, a stable mimic of Ca2+-mobilizing second messenger cyclic ADP-ribose
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DOI：
10.1021/ja010756d
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发表时间：
2001-09-12
影响因子：
15
通讯作者：
Matsuda, A
中科院分区：
文献类型：
--
作者：
Shuto, S;Fukuoka, M;Matsuda, A
环状ADP-碳环-核糖（cADPcR，4）的合成被设计为环状ADP-核糖（cADPR，1）（一种Ca 2+动员第二信使）的稳定模拟物，其使用与苯硫代磷酸盐型底物14的缩合反应以形成分子内焦磷酸连接作为关键步骤来实现。N-1-碳环-核糖基腺苷衍生物16是通过由AICA-核苷（19）制备的咪唑核苷衍生物17与易得的光学活性碳环胺18之间的缩合反应制备的。然后将化合物16转化为相应的5“-磷酰基-5 '苯基硫代磷酸酯衍生物14。在分子筛（3 A）的存在下，在吡啶中，在室温下用AgNO 3处理14，以93%的产率得到所需的环化产物32，随后的酸处理提供目标cADPcR（4）。这代表了合成这种类型的生物学重要的环核苷酸的一般方法。cADPcR在水溶液中的构象与cADPR相似。cADPcR。与cADPR不同。在中性和酸性条件下稳定，在碱性条件下稳定。它形成Dimroth重排的N-6-环化产物34。cADPcR在具有cADPR降解活性的大鼠脑组织匀浆中也是稳定的。此外，cADPcR对CD 38 cADPR水解酶的水解具有抗性。而cADPR在相同条件下迅速水解。当cADPcR注射到海胆卵中时，它引起细胞中Ca 2+的显著释放，其效果比cADPR强得多。因此，cADPcR被鉴定为cADPR的稳定模拟物。
The synthesis of cyclic ADP-carbocyclic-ribose (cADPcR, 4) designed as a stable mimic of cyclic ADP-ribose (cADPR, 1), a Ca2+-mobilizing second messenger, was achieved using as the key step a condensation reaction with the phenylthiophosphate-type substrate 14 to form an intramolecular pyrophosphate linkage. The N-1-carbocyclic-ribosyladenosine derivative 16 was prepared via the condensation between the imidazole nucleoside derivative 17, prepared from AICA-riboside (19), and the readilv available optically active carbocyclic amine 18. Compound 16 was then converted to the corresponding 5 " -phosphoryl-5 ' phenylthiophosphate derivatives 14. Treatment of 14 with AgNO3 in the presence of molecular sieves (3 A) in pyridine at room temperature gave the desired cyclization product 32 in 93% yield, and subsequent acidic treatment provided the target cADPcR (4), This represents a general method for synthesizing biologically important cyclic nucleotides of this type. H-1 NMR analysis of cADPcR suggested that its conformation in aqueous medium is similar to that of cADPR. cADPcR. unlike cADPR. was stable under neutral and acidic conditions, where under basic conditions. it formed the Dimroth-rearranged N-6-cyclized product 34. cADPcR was also stable in rat brain membrane homogenate which has cADPR degradation activity. Furthermore, cADPcR was resistant to the hydrolysis by CD38 cADPR hydrolase. while cADPR was rapidly hydrolyzed under the same conditions. When cADPcR was injected into sea urchin eggs, it caused a significant release of Ca2+ in the cells, an effect considerably stronger than that of cADPR. Thus, cADPcR was identified as a stable mimic of cADPR.