| 1310716-28-9

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘌呤核苷酸
• CAS: 1310716-28-9
• 化学式: C₄₅H₆₆IN₁₃O₁₅P₂SSi₂
• 分子量: 1306.19
• InChiKey: CTGZGFHSHQQEJP-IFJDAXDKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.09
• 重原子数：
  79.0
• 可旋转键数：
  25.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  366.08
• 氢给体数：
  4.0
• 氢受体数：
  25.0

反应信息

• 作为反应物：
  描述：

  、 triethylamine tris(hydrogen fluoride) 在 ammonium hydroxide 、 吡啶 作用下， 以 水 、 乙腈 为溶剂， 反应 24.0h， 以59%的产率得到
  参考文献：
  名称：

  Conservative Change to the Phosphate Moiety of Cyclic Diguanylic Monophosphate Remarkably Affects Its Polymorphism and Ability To Bind DGC, PDE, and PilZ Proteins

  摘要：

  The cyclic dinucleotide c-di-GMP is a master regulator of bacterial virulence and biofilm formation. The activations of c-di-GMP metabolism proteins, diguanylate cyclases (DGCs) and phosophodiesterases (PDEs), usually lead to diametrically opposite phenotypes in bacteria. Analogues of c-di-GMP, which can selectively modulate the activities of c-di-GMP processing proteins, will be useful chemical tools for studying and altering bacterial behavior. Herein we report that a conservative modification of one of the phosphate groups in c-di-GMP with a bridging sulfur in the phosphodiester linkage affords an analogue called endo-S-c-di-GMP. Computational, NMR (including DOSY), and CD experiments all reveal that, unlike c-di-GMP, endo-S-c-di-GMP does not readily form higher aggregates. The lower propensity of endo-S-c-di-GMP to form aggregates (as compared to that of c-di-GMP) is probably due to a higher activation barrier to convert from the "open" conformer (where the two guanines are on opposite faces) to the "closed" conformer (where the two guanines are on the same face). Consequently, endo-S-c-di-GMP has selectivity for proteins that bind monomeric but not dimeric c-di-GMP, which form from the "closed" conformer. For example, endo-S-c-di-GMP can inhibit the hydrolysis of c-di-GMP by RocR (a PDE enzyme that binds monomeric c-di-GMP) but did not bind to A1g44 (a PilZ protein) or regulate WspR (a DGC enzyme that has been shown to bind to dimeric c-di-GMP). This work demonstrates that selective binding to different classes of c-di-GMP binding proteins could be achieved by altering analogue conformer populations (conformational steering). We provide important design principles for the preparation of selective PDE inhibitors and reveal the role played by the c-di-GMP backbone in c-di-GMP polymorphism and binding to processing proteins.

  DOI：

  10.1021/ja1112029
• 作为产物：
  描述：

  在 2,6-二甲基吡啶 、 甲基三苯氧基碘磷 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 以0.42 g的产率得到
  参考文献：
  名称：

  Conservative Change to the Phosphate Moiety of Cyclic Diguanylic Monophosphate Remarkably Affects Its Polymorphism and Ability To Bind DGC, PDE, and PilZ Proteins

  摘要：

  The cyclic dinucleotide c-di-GMP is a master regulator of bacterial virulence and biofilm formation. The activations of c-di-GMP metabolism proteins, diguanylate cyclases (DGCs) and phosophodiesterases (PDEs), usually lead to diametrically opposite phenotypes in bacteria. Analogues of c-di-GMP, which can selectively modulate the activities of c-di-GMP processing proteins, will be useful chemical tools for studying and altering bacterial behavior. Herein we report that a conservative modification of one of the phosphate groups in c-di-GMP with a bridging sulfur in the phosphodiester linkage affords an analogue called endo-S-c-di-GMP. Computational, NMR (including DOSY), and CD experiments all reveal that, unlike c-di-GMP, endo-S-c-di-GMP does not readily form higher aggregates. The lower propensity of endo-S-c-di-GMP to form aggregates (as compared to that of c-di-GMP) is probably due to a higher activation barrier to convert from the "open" conformer (where the two guanines are on opposite faces) to the "closed" conformer (where the two guanines are on the same face). Consequently, endo-S-c-di-GMP has selectivity for proteins that bind monomeric but not dimeric c-di-GMP, which form from the "closed" conformer. For example, endo-S-c-di-GMP can inhibit the hydrolysis of c-di-GMP by RocR (a PDE enzyme that binds monomeric c-di-GMP) but did not bind to A1g44 (a PilZ protein) or regulate WspR (a DGC enzyme that has been shown to bind to dimeric c-di-GMP). This work demonstrates that selective binding to different classes of c-di-GMP binding proteins could be achieved by altering analogue conformer populations (conformational steering). We provide important design principles for the preparation of selective PDE inhibitors and reveal the role played by the c-di-GMP backbone in c-di-GMP polymorphism and binding to processing proteins.

  DOI：

  10.1021/ja1112029