1-((1S,3S,4S,5S)-3-Azido-4-hydroxymethyl-bicyclo[3.1.0]hex-1-yl)-5-methyl-1H-pyrimidine-2,4-dione | 205868-78-6

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 核苷和核苷酸类似物
• 英文名称: 1-((1S,3S,4S,5S)-3-Azido-4-hydroxymethyl-bicyclo[3.1.0]hex-1-yl)-5-methyl-1H-pyrimidine-2,4-dione
• 英文别名: 1-[(1S,3S,4S,5S)-3-azido-4-(hydroxymethyl)-1-bicyclo[3.1.0]hexanyl]-5-methylpyrimidine-2,4-dione
• CAS: 205868-78-6
• 化学式: C₁₂H₁₅N₅O₃
• 分子量: 277.283
• InChiKey: KULDHWYURHNUTK-PEFMBERDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  20
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  84
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-((1S,3S,4S,5S)-3-Azido-4-hydroxymethyl-bicyclo[3.1.0]hex-1-yl)-5-methyl-1H-pyrimidine-2,4-dione 在 三丁基焦磷酸铵 、 三氯氧磷 作用下， 生成 (S)-methano-carba-AZT 5'-triphosphate
  参考文献：
  名称：

  Lessons from the Pseudorotational Cycle: Conformationally Rigid AZT Carbocyclic Nucleosides and Their Interaction with Reverse Transcriptase

  摘要：

  Two conformationally locked carba-AZT nucleoside 5'-triphosphates built on a rigid bicyclo[3.1.0]hexane template showed exclusive Northern (E-2) and Southern (E-3) conformations, respectively. Inhibition of reverse transcriptase (RT) occurred selectively with the Northern carba-AZT triphosphate.

  DOI：

  10.1080/07328319808004726
• 作为产物：
  描述：

  Benzoic acid (1S,2R,3R,5S)-3-methanesulfonyloxy-5-(5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-bicyclo[3.1.0]hex-2-ylmethyl ester 在 叠氮化锂 、 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 1-((1S,3S,4S,5S)-3-Azido-4-hydroxymethyl-bicyclo[3.1.0]hex-1-yl)-5-methyl-1H-pyrimidine-2,4-dione
  参考文献：
  名称：

  Lessons from the Pseudorotational Cycle: Conformationally Rigid AZT Carbocyclic Nucleosides and Their Interaction with Reverse Transcriptase

  摘要：

  Two conformationally locked carba-AZT nucleoside 5'-triphosphates built on a rigid bicyclo[3.1.0]hexane template showed exclusive Northern (E-2) and Southern (E-3) conformations, respectively. Inhibition of reverse transcriptase (RT) occurred selectively with the Northern carba-AZT triphosphate.

  DOI：

  10.1080/07328319808004726

文献信息

• HIV-1 Reverse Transcriptase Can Discriminate between Two Conformationally Locked Carbocyclic AZT Triphosphate Analogues
  作者：Victor E. Marquez、Abdallah Ezzitouni、Pamela Russ、Maqbool A. Siddiqui、Harry Ford,、Ron J. Feldman、Hiroaki Mitsuya、Clifford George、Joseph J. Barchi

  DOI：10.1021/ja973535+

  日期：1998.4.1

  It has been proposed that the preference of 3'-azido-3'-deoxythymidine (AZT) for the extreme E-3 (south) conformation, as observed in its X-ray structure, is responsible for its potent anti-HIV activity. However, it has also been suggested that the antipodal north conformation may be required for the strong interaction of AZT 5'-triphosphate with its target enzyme, HIV reverse transcriptase (RT). To resolve this issue, we have constructed two conformationally rigid carbocyclic analogues of AZT which are locked permanently into opposite E-2 (north) and E-3 (south) conformations in order to test the ability of the corresponding 5'-triphosphates to inhibit RT. The two isomeric carbocyclic analogues of AZT, (N)-methano-carba-AZT (1) and (S)-methano-carba-AZT (2), were constructed on a bicyclo[3.1.0]hexane template that exhibits a rigid pseudoboat conformation, capable of mimicking the furanose pucker in the classical north and south conformations that are characteristic of standard nucleosides. The unique conformational properties of 1 and 2 observed by both X-ray and solution NMR studies showed the existence of the same invariant conformations in solution and in the solid state. In addition, differences observed in the outcome of the Mitsunobu inversion of a secondary hydroxyl function attempted with both bicyclo[3.1.0]hexane nucleoside analogues could be explained by the rigid pseudoboat nature of this system. In one case, the bicyclic system facilitated formation of an anhydronucleoside intermediate, whereas in the other it completely prevented its formation. The chemically synthesized 5'-triphosphates of 1 and 2 were evaluated directly as RT inhibitors using both a recombinant enzyme and enzyme obtained and purified directly from wild-type viruses. The results showed that inhibition of RT occurred only with the conformationally locked E-2 (N)-methano-carba-AZT 5'-triphosphate. This inhibition was equipotent to and kinetically indistinguishable from that produced by AZT 5'-triphosphate. The antipodal E-3 (S)-methano-carba-AZT 5'-triphosphate, on the other hand, did not inhibit RT.