Nucleosides and nucleotides.: 173.: Synthesis of cyclic IDP-carbocyclic-ribose, a stable mimic of cyclic ADP-ribose.: Significant facilitation of the intramolecular condensation reaction of N-1-(carbocyclic-ribosyl)inosine 5′,6"-diphosphate derivatives by an 8-bromo-substitution at the hypoxanthine moiety
Nucleosides and nucleotides.: 173.: Synthesis of cyclic IDP-carbocyclic-ribose, a stable mimic of cyclic ADP-ribose.: Significant facilitation of the intramolecular condensation reaction of N-1-(carbocyclic-ribosyl)inosine 5′,6"-diphosphate derivatives by an 8-bromo-substitution at the hypoxanthine moiety
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DOI：
10.1021/jo9717797
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发表时间：
1998-03-20
影响因子：
3.6
通讯作者：
Matsuda, A
中科院分区：
文献类型：
--
作者：
Shuto, S;Shirato, M;Matsuda, A
环腺苷二磷酸核糖（cADPR，1）是参与细胞内钙信号转导的一种重要介质。然而，cADPR的生物学和化学不稳定性限制了其生理作用的研究。我们设计了环状ADP-碳环-核糖（3）及其肌苷同系物4作为cADPR的稳定模拟物，并成功地合成了4。从环戊二烯开始，通过酶促光学拆分构建光学活性碳环单元8。8与次黄嘌呤核苷衍生物7和8-溴次黄嘌呤核苷衍生物25发生S（N）2反应，得到N-1-取代的衍生物6和26，它们被转化为相应的二磷酸衍生物5和22。研究了5和22的两个磷酸基团之间的分子内缩合反应。虽然与肌苷衍生物5的反应不产生任何环化产物20，但用EDC处理相应的8-溴肌苷衍生物22以23%的产率得到所需的分子内缩合产物29。因此，认识到次黄嘌呤部分的8-溴基团在促进底物22的磷酸基团之间的关键分子内缩合反应中的显著作用。这可能是由于分子在其糖基连接周围的顺式构象限制。依次除去8-溴和异亚丙基，得到目标化合物4。这是第一次全合成这种类型的环核苷酸。
Cyclic ADP-ribose (cADPR, 1) is a general mediator involved in cellular Ca2+ signaling. However, both the biological and chemical instability of cADPR limit studies on its physiological role. We designed cyclic ADP-carbocyclic-ribose (3) and its inosine congener 4 as stable mimics of cADPR and successfully synthesized 4. Starting with cyclopentadiene, the optically active carbocyclic unit 8 was constructed via enzymatic optical resolution. S(N)2 reactions of 8 with inosine derivative 7 and the 8-bromoinosine derivative 25 gave the N-1-substituted derivatives 6 and 26, which were converted to the corresponding diphosphate derivatives 5 and 22. The intramolecular condensation reactions between the two phosphate groups of 5 and 22 were investigated, Although the reaction with inosine derivative 5 did not produce any of the cyclization product 20, treatment of the corresponding 8-bromoinosine derivative 22 with EDC gave the desired intramolecular condensation product 29 in 23% yield. Thus, the significant effect of the 8-bromo group at the hypoxanthine moiety in facilitating the key intramolecular condensation reaction between the phosphate groups of the substrate 22 was recognized. This is possibly due to conformational restriction of the molecule in a syn-form around its glycosyl linkage. The 8-bromo and isopropylidene groups were removed in succession to give the target compound 4. This is the first total synthesis of this type of cyclic nucleotide.