(N)-2'-deoxy-methanocarba-U | 181935-38-6

• 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: (N)-2'-deoxy-methanocarba-U
• 英文别名: 1-[(1S,2S,4S,5R)-4-hydroxy-5-(hydroxymethyl)-2-bicyclo[3.1.0]hexanyl]pyrimidine-2,4-dione
• CAS: 181935-38-6
• 化学式: C₁₁H₁₄N₂O₄
• 分子量: 238.243
• InChiKey: XUORZQLPFYEVFJ-GLLZPBPUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.8
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.64
• 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：

  (N)-2'-deoxy-methanocarba-U 在 吡啶 、 ammonium hydroxide 、 三乙胺 、 三氯氧磷 作用下， 以 1,4-二氧六环 、 乙腈 为溶剂， 反应 2.0h， 生成 Acetic acid (1R,2S,4S,5S)-1-acetoxymethyl-4-(4-amino-2-oxo-2H-pyrimidin-1-yl)-bicyclo[3.1.0]hex-2-yl ester
  参考文献：
  名称：

  核苷有扭曲。固定形式的糖环褶皱会影响核苷和寡核苷酸中的生物活性吗？

  摘要：

  已知溶液中核苷的糖部分以假旋转循环中定义的极端北部和南部构象之间的快速动态平衡存在。在当前的工作中，我们描述了双环[3.1.0]己烷模板如何将2'-脱氧-甲氨基甲酸酯-核苷1-5和12的环褶皱固定为与以下两个典型的极端构型之一相对应的值：核苷。固定的Northern构象1-5的合成是通过杂环基与手性碳环醇6 [[（1R，2S，4R，5S）-1-[（苄氧基）甲基] -2-（叔-丁氧基）-4-羟基ybicyclo [3.1.0]己烷]，而较早报道了南部构象异构体（S）-甲氨基甲酸酯-T（12）的合成。碳环胸苷（carba-T，13）作为参考，柔性碳环核苷。对这些化合物的抗病毒评价表明，它与北胸腺嘧啶核苷类似物2有关，具有很强的抗疱疹活性，它比参考标准阿昔洛韦对HSV-1和HSV-2的作用更强。（N）-Methanocarba-T（2）被进一步评估为短硫代脱氧核苷酸（ODN）硫代磷酸酯（5'-C

  DOI：

  10.1021/jm960306+
• 作为产物：
  描述：

  (1S,2S,4S,5R)-N-((2E)-ethoxyprop-2-enoyl)({4-hydroxy-5-[(phenylmethoxy)methyl]bicyclo[3.1.0]hex-2-yl}amino)carboxamide 在 硫酸 、 三氯化硼 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 反应 1.0h， 生成 (N)-2'-deoxy-methanocarba-U
  参考文献：
  名称：

  Synthesis and Biological Evaluation of 5-Substituted Derivatives of the Potent Antiherpes Agent (north)-Methanocarbathymine

  摘要：

  The conformationally locked nucleoside, (north)-methanocarbathymine (1a), is a potent and selective anti-herpes agent effective against herpes simplex type I (HSV1) and type 2 (HSV2) viruses. Hereby, we report on the synthesis and biological evaluation of a small set of 5-substituted pyrimidine nucleosides belonging to the same class of bicyclo[3.1.0]hexane nucleosides. Both the 5-bromovinyl (4) and the 5-bromo analogue (3) appeared to be exclusive substrates of HSV1 thymidine kinase (TK), contrasting with the 5-iodo analogue (2), which was significantly phosphorylated by the human cytosolic TK. The binding affinity constant and catalytic turnover for HSV1 TK were measured to assess the influence of the substitution on these parameters. In the plaque reduction and cytotoxicity assays, the 5-bromo analogue (3) showed good activity against HSV1 and HSV2 with less general toxicity than la. Against varicella-zoster virus (VZV), the north-locked 5-bromovinyl analogue (4) proved to be as potent as its conformationally unlocked 2'-deoxyriboside equivalent BVDU. The three compounds were also tested in vitro as prodrugs used in a gene therapy context on three osteosarcoma cell lines, either deficient in TK (TK-), nontransduced, or stably transduced with HSV1 TK. The 5-iodo compound (2, CC50 25 +/- 7 muM) was more efficient than ganciclovir (GCV, CC50 75+/-35 muM) in inhibiting growth of HSV1-TK transfected cells and less inhibitory than GCV toward TK- cells, whereas compound 3 inhibited transfected and nontransfected cell lines in a relatively similar dose-dependent manner.

  DOI：

  10.1021/jm030241s

文献信息

• Contrasting Behavior of Conformationally Locked Carbocyclic Nucleosides of Adenosine and Cytidine as Substrates for Deaminases
  作者：Victor E. Marquez、Gottfried K. Schroeder、Olaf R. Ludek、Maqbool A. Siddiqui、Abdallah Ezzitouni、Richard Wolfenden

  DOI：10.1080/15257770903091904

  日期：2009.8.11

  In addition to the already known differences between adenosine deaminase (ADA) and cytidine deaminase (CDA) in terms of their tertiary structure, the sphere of Zn+2 coordination, and their reverse stereochemical preference, we present evidence that the enzymes also differ significantly in terms of the North/South conformational preferences for their substrates and the extent to which the lack of the

  除了已知的腺苷脱氨酶 (ADA) 和胞苷脱氨酶 (CDA) 在三级结构、Zn+2 配位范围和反向立体化学偏好方面存在差异之外，我们还提供了证据表明这些酶在其底物的北/南构象偏好以及缺乏 O(4') 氧对碳环底物酶促脱氨动力学的影响程度。本研究中使用的碳环核苷底物具有柔性环戊烷环或刚性双环 [3.1.0] 己烷支架。
• [EN] CONFORMATIONALLY LOCKED NUCLEOSIDE ANALOGS AS ANTIHERPETIC AGENTS<br/>[FR] ANALOGUES DE NUCLEOSIDES A BLOCAGE CONFORMATIONNEL EN TANT QU'AGENTS ANTIHERPETIQUES
  申请人：THE GOVERNMENT OF THE UNITED STATES OF AMERICA, represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES

  公开号：WO1998005662A1

  公开（公告）日：1998-02-12

  (EN) A method for treatment of herpes virus infection by administering an effective virus-inhibiting amount of a cyclopropanated carbocyclic 2'-deoxynucleoside to an individual in need thereof. The nucleoside analogs are effective against herpes simplex virus types 1 and 2; Epstein-Barr Virus and human cytomegalovirus.(FR) Procédé de traitement de l'infection due à l'herpèsvirus, qui consiste à administrer une quantité, efficace pour inhiber le virus, d'un 2'-désoxynucléoside carbocyclique cyclopropané à un patient ayant besoin dudit traitement. Lesdits analogues de nucléoside sont efficaces contre l'herpès simplex de type 1 et 2, le virus d'Epstein-Barr et le cytomégalovirus humain.
• Nucleosides with a Twist. Can Fixed Forms of Sugar Ring Pucker Influence Biological Activity in Nucleosides and Oligonucleotides?
  作者：Victor E. Marquez、Maqbool A. Siddiqui、Abdallah Ezzitouni、Pamela Russ、Jianying Wang、Richard W. Wagner、Mark D. Matteucci

  DOI：10.1021/jm960306+

  日期：1996.1.1

  of the pseudosugar rings into a Northern conformation, typical of A-DNA, was evident by the increase in Tm of the corresponding DNA/RNA heteroduplex. However, the rigid A-tract ODN caused loss of RNase H recruitment. A detailed conformational analysis of (N)-methanocarba-T (2) and (S)-methanocarba-T (12), as representative examples of conformationally rigid pseudorotational antipodes, revealed that

  已知溶液中核苷的糖部分以假旋转循环中定义的极端北部和南部构象之间的快速动态平衡存在。在当前的工作中，我们描述了双环[3.1.0]己烷模板如何将2'-脱氧-甲氨基甲酸酯-核苷1-5和12的环褶皱固定为与以下两个典型的极端构型之一相对应的值：核苷。固定的Northern构象1-5的合成是通过杂环基与手性碳环醇6 [[（1R，2S，4R，5S）-1-[（苄氧基）甲基] -2-（叔-丁氧基）-4-羟基ybicyclo [3.1.0]己烷]，而较早报道了南部构象异构体（S）-甲氨基甲酸酯-T（12）的合成。碳环胸苷（carba-T，13）作为参考，柔性碳环核苷。对这些化合物的抗病毒评价表明，它与北胸腺嘧啶核苷类似物2有关，具有很强的抗疱疹活性，它比参考标准阿昔洛韦对HSV-1和HSV-2的作用更强。（N）-Methanocarba-T（2）被进一步评估为短硫代脱氧核苷酸（ODN）硫代磷酸酯（5'-C
• Synthesis and Biological Evaluation of 5-Substituted Derivatives of the Potent Antiherpes Agent (north)-Methanocarbathymine
  作者：Pamela Russ、Pierre Schelling、Leonardo Scapozza、Gerd Folkers、Erik De Clercq、Victor E. Marquez

  DOI：10.1021/jm030241s

  日期：2003.11.1

  The conformationally locked nucleoside, (north)-methanocarbathymine (1a), is a potent and selective anti-herpes agent effective against herpes simplex type I (HSV1) and type 2 (HSV2) viruses. Hereby, we report on the synthesis and biological evaluation of a small set of 5-substituted pyrimidine nucleosides belonging to the same class of bicyclo[3.1.0]hexane nucleosides. Both the 5-bromovinyl (4) and the 5-bromo analogue (3) appeared to be exclusive substrates of HSV1 thymidine kinase (TK), contrasting with the 5-iodo analogue (2), which was significantly phosphorylated by the human cytosolic TK. The binding affinity constant and catalytic turnover for HSV1 TK were measured to assess the influence of the substitution on these parameters. In the plaque reduction and cytotoxicity assays, the 5-bromo analogue (3) showed good activity against HSV1 and HSV2 with less general toxicity than la. Against varicella-zoster virus (VZV), the north-locked 5-bromovinyl analogue (4) proved to be as potent as its conformationally unlocked 2'-deoxyriboside equivalent BVDU. The three compounds were also tested in vitro as prodrugs used in a gene therapy context on three osteosarcoma cell lines, either deficient in TK (TK-), nontransduced, or stably transduced with HSV1 TK. The 5-iodo compound (2, CC50 25 +/- 7 muM) was more efficient than ganciclovir (GCV, CC50 75+/-35 muM) in inhibiting growth of HSV1-TK transfected cells and less inhibitory than GCV toward TK- cells, whereas compound 3 inhibited transfected and nontransfected cell lines in a relatively similar dose-dependent manner.