2,4(1H,3H)-嘧啶二酮,1-[(1S,3S,4R,5S)-3-羟基-4-(羟甲基)二环[3.1.0]己-1-基]-5-甲基- | 156044-00-7

• 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
• 中文名称: 2,4(1H,3H)-嘧啶二酮,1-[(1S,3S,4R,5S)-3-羟基-4-(羟甲基)二环[3.1.0]己-1-基]-5-甲基-
• 英文名称: (S)-Methanocarba-Thymidine
• 英文别名: (South)-methanocarba-thymidine；1-[(1S,3S,4R,5S)-3-hydroxy-4-(hydroxymethyl)-1-bicyclo[3.1.0]hexanyl]-5-methylpyrimidine-2,4-dione
• CAS: 156044-00-7
• 化学式: C₁₂H₁₆N₂O₄
• 分子量: 252.27
• InChiKey: XRMLXZVSFIBRRJ-PEFMBERDSA-N

物化性质

• 密度：
  1.490±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.5
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  89.9
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2,4(1H,3H)-嘧啶二酮,1-[(1S,3S,4R,5S)-3-羟基-4-(羟甲基)二环[3.1.0]己-1-基]-5-甲基- 在 吡啶 、 4-二甲氨基吡啶 、 叠氮化锂 、 potassium carbonate 、 三乙胺 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 N,N-二甲基甲酰胺 、 乙腈 、 苯 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
• 作为产物：
  描述：

  (1S,2R,3R,4R)-1-Benzyloxy-2-benzyloxymethyl-4-cyano-3-hydroxycyclopentane 在 钯 盐酸 、 4-二甲氨基吡啶 、 sodium hydroxide 、 甲酸 、 二苯甲酮 、 二苯基磷酸 、 四丁基氟化铵 、 三乙胺 、 N,N'-硫羰基二咪唑 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 乙醇 、 二氯甲烷 、 氯仿 、 N,N-二甲基甲酰胺 、 甲苯 、 乙腈 、 苯 为溶剂， 反应 167.5h， 生成 2,4(1H,3H)-嘧啶二酮,1-[(1S,3S,4R,5S)-3-羟基-4-(羟甲基)二环[3.1.0]己-1-基]-5-甲基-
  参考文献：
  名称：

  Conformationally locked carbocyclic nucleosides built on a bicyclo[3.1.0]hexane template with a fixed Southern conformation. Synthesis and antiviral activity

  摘要：

  具有固定结构的碳环核苷的构建 3E 南半球环皱褶 伪旋转循环是由共同的前体碳环实现的 胺， (1S,3S,4R,5 S )-3-苄氧基-4-苄氧基甲基-1-氨基双环[3.1.0]己烷 20. 这个 碳环胺由光学纯高效组装而成 2-苄氧基甲基环戊-3-烯醇 11 十步反应。关键 环丙烷化步骤进行于 (3R,4S )-1-氰基-4-苄氧基-3-(苄氧基甲基)环戊烷15，并进行 区域和立体选择性地给出关键的氰基碳环 中间体17，随后由其获得胺20。 嘧啶类似物 6-8 的合成完成 通过中间体无环丙烯酰脲21和22。 需要事先准备嘌呤 9 和 10 相应的N-甲酰化 4,6-二氯-5-氨基嘧啶和4,6-二氯-2,5-二氨基嘧啶 与胺20有效偶联的杂环前体。除了 (S)-2′-脱氧甲烷碳-A （9，2′-脱氧腺苷类似物），所有南方构象异构体 似乎缺乏抗病毒活性。

  DOI：

  10.1039/a604352f

文献信息

• [EN] ANTI-VIRAL AND HEPATIC-TARGETED DRUGS<br/>[FR] MÉDICAMENTS ANTIVIRAUX ET CIBLÉS SUR LE FOIE
  申请人：AI BIOPHARMA

  公开号：WO2021074443A1

  公开（公告）日：2021-04-22

  Disclosed herein are identified compound fragments, compounds and their pharmaceutically acceptable salts, isotopes or solvates, useful as antiviral drug and/or as a hepatic-targeted drug, such as for the treatment of HBV, HDV and/or HIV. Formula (I).

  本文揭示了被识别的化合物片段、化合物及其药学上可接受的盐、同位素或溶剂化合物，用作抗病毒药物和/或肝靶向药物，例如用于治疗HBV、HDV和/或HIV。公式（I）。
• A simple approach to 1′,1′a-methano carbocyclic thymidine
  作者：Abdallah Ezzitouni、Joseph J. Barchi、Victor E. Marquez

  DOI：10.1039/c39950001345

  日期：——

  An enantioselective synthesis of 1′,1′a-methano carbocyclic thymidine, a rigid molecule that mimics thymidine's 2′-endo/3′-exo(South) conformation, is efficiently synthesized from chiral 2-benzyloxymethylcyciopent-3-enol.

  以手性 2-苄氧基甲基环戊-3-烯醇为原料，高效合成了 1â²,1â²a-甲烷碳环胸苷，这是一种模仿胸苷 2â²-内/3â²-外（南）构象的刚性分子。
• North-2'deoxy -methanocarbathymidines as antiviral agents for treatment of kaposi's sarcoma-associated herpes virus
  申请人：Sei Shizuko

  公开号：US20090192077A1

  公开（公告）日：2009-07-30

  A method for the prevention or treatment of Kaposi's sarcoma or Kaposi's sarcoma-associated herpes virus infection by administering an effective amount of a cyclopropanated carbocyclic 2′-deoxynucleoside to an individual in need thereof is provided.

  本发明提供了一种通过向需要的个体施用有效量的环丙基化的碳环2'-脱氧核苷来预防或治疗卡波西肉瘤或卡波西肉瘤相关的单纯疱疹病毒感染的方法。
• 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.
• 1′,6′-methano carbocyclic thymidine: Synthesis, x-ray crystal structure, and effect on nucleic acid duplex stability
  作者：Karl-Heinz Altmann、René Imwinkelried、Rudolf Kesselring、Grety Rihs

  DOI：10.1016/s0040-4039(00)78359-6

  日期：1994.10

  The title compound 1 has been synthesized via bicyclic lactone 3 and amine 9 as the key intermediates. X-ray crystallography reveals the bicyclic skeleton of 1 to adopt a boat-like (3'exo) conformation. Oligodeoxyribonucleotides incorporating up to 10 building blocks 1 in place of natural thymidine are still capable of binding to complementary DNA or RNA, albeit with lower affinity than the unmodified parent compounds.