(1S,2S,4S,5R)-1-{4-hydroxy-5-[(phenylmethoxy)methyl]bicyclo[3.1.0]hex-2-yl}-1,3-dihydropyrimidine-2,4-dione | 391679-37-1

• 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: (1S,2S,4S,5R)-1-{4-hydroxy-5-[(phenylmethoxy)methyl]bicyclo[3.1.0]hex-2-yl}-1,3-dihydropyrimidine-2,4-dione
• 英文别名: 1-[(1S,2S,4S,5R)-4-hydroxy-5-(phenylmethoxymethyl)-2-bicyclo[3.1.0]hexanyl]pyrimidine-2,4-dione
• CAS: 391679-37-1
• 化学式: C₁₈H₂₀N₂O₄
• 分子量: 328.368
• InChiKey: JOWQPNNDUKOZSD-LLDVTBCESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  24
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  78.9
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (1S,2S,4S,5R)-1-{4-hydroxy-5-[(phenylmethoxy)methyl]bicyclo[3.1.0]hex-2-yl}-1,3-dihydropyrimidine-2,4-dione 在 溴 、 三氯化硼 作用下， 以 二氯甲烷 为溶剂， 反应 0.5h， 生成 (1R,2S,4S,5S)-[2-acetyloxy-4-(5-bromo-2,4-dioxo(1,3-dihydropyrimidinyl))bicyclo[3.1.0]hexyl]methyl acetate
  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
• 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 作用下， 以 乙醇 为溶剂， 反应 1.0h， 以73%的产率得到(1S,2S,4S,5R)-1-{4-hydroxy-5-[(phenylmethoxy)methyl]bicyclo[3.1.0]hex-2-yl}-1,3-dihydropyrimidine-2,4-dione
  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

• 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.