1-[(1R,2R,5S)-5-[[tert-butyl(diphenyl)silyl]oxymethyl]-2-bicyclo[3.1.0]hex-3-enyl]-5-methylpyrimidine-2,4-dione | 917483-18-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 1-[(1R,2R,5S)-5-[[tert-butyl(diphenyl)silyl]oxymethyl]-2-bicyclo[3.1.0]hex-3-enyl]-5-methylpyrimidine-2,4-dione
• CAS: 917483-18-2
• 化学式: C₂₈H₃₂N₂O₃Si
• 分子量: 472.659
• InChiKey: QSDPPRNBBVSYDS-JPYHZWLXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.54
• 重原子数：
  34
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  58.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-[(1R,2R,5S)-5-[[tert-butyl(diphenyl)silyl]oxymethyl]-2-bicyclo[3.1.0]hex-3-enyl]-5-methylpyrimidine-2,4-dione 在 palladium on activated charcoal 四丁基氟化铵 、 氢气 作用下， 以 四氢呋喃 为溶剂， 生成 (1'R,2'R,5'S)-1-[5-(hydroxymethyl)bicyclo[3.1.0]hex-2-yl]-5-methyl-1,3-dihydropyrimidine-2,4-dione
  参考文献：
  名称：

  Understanding How the Herpes Thymidine Kinase Orchestrates Optimal Sugar and Nucleobase Conformations To Accommodate Its Substrate at the Active Site:  A Chemical Approach

  摘要：

  The herpes virus thymidine kinase (HSV-tk) is a critical enzyme for the activation of anti-HSV nucleosides. However, a successful therapeutic outcome depends not only on the activity of this enzyme but also on the ability of the compound(s) to interact effectively with cellular kinases and with the target viral or cellular DNA polymerases. Herein, we describe the synthesis and study of two nucleoside analogues built on a conformationally locked bicyclo[3.1.0]hexane template designed to investigate the conformational preferences of HSV-tk for the 2'-deoxyribose ring. Intimately associated with the conformation of the 2'deoxyribose ring is the value of the C-N torsion angle chi, which positions the nucleobase into two different domains (syn or anti). The often-conflicting sugar and nucleobase conformational parameters were studied using North and South methanocarbadeoxythymidine analogues (6 and 7), which forced HSV-tk to make a clear choice in the conformation of the substrate. The results provide new insights into the mechanism of action of this enzyme, which cannot be gleaned from a static X-ray crystal structure.

  DOI：

  10.1021/ja053789s
• 作为产物：
  描述：

  N-3-benzoylthymine 在 ammonium hydroxide 、 水 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 5.0h， 生成 1-[(1R,2R,5S)-5-[[tert-butyl(diphenyl)silyl]oxymethyl]-2-bicyclo[3.1.0]hex-3-enyl]-5-methylpyrimidine-2,4-dione
  参考文献：
  名称：

  对映体纯d-和l-双环[3.1.0]己烯基碳核苷的合成及其抗病毒评价

  摘要：

  基于已知l-核苷的细胞毒性比d-对应物低的事实，通过采用从 ( R )-表氯醇，以寻找具有高效力和较低细胞毒性的新型抗 HIV 药物。串联烷基化、γ-内酯化、在γ-内酯官能团存在下化学选择性还原酯、RCM反应和Mitsunobu偶联反应被用作关键反应。d-对应的核苷也根据相同的合成方法制备。在合成的碳核苷中， d-胸腺嘧啶核苷、d - 2和l-胸腺嘧啶核苷、l - 2在 MT-4 细胞中表现出优异的抗 HIV-1 和 -2 活性，高于 ddI，一种抗-艾滋病药物。虽然d - 2在 MT-4 细胞系中表现出高细胞毒性，但l - 2在所有测试的细胞系中均未显示出任何可辨别的细胞毒性，这表明l - 2可能是抗艾滋病药物的良好候选者。l -2也显示出弱的抗HSV-2活性而没有细胞毒性。然而，合成的核苷都没有表现出对包括柯萨奇病毒、流感病毒、冠状病毒和脊髓灰质炎病毒在内的 RNA 病毒的抗病毒活性，这可能是由于它们的

  DOI：

  10.1016/j.bmc.2011.05.026

文献信息

• Synthesis of novel l-N-MCd4T as a potent anti-HIV agent
  作者：Ah-Young Park、Hyung Ryong Moon、Kyung Ran Kim、Moon Woo Chun、Lak Shin Jeong

  DOI：10.1039/b612537a

  日期：——

  L-N-MCd4T (1) has been synthesized as a potent anti-HIV agent starting from (R)-epichlorohydrin using tandem alkylation, chemoselective reduction of ester in the presence of lactone functional group, RCM reaction and Mitsunobu reaction as key steps and was found to be a very potent anti-HIV-1 (EC50 = 6.76 µg mL−1) agent without cytotoxicity up to 100 µg mL−1, indicating that the anti-HIV-1 activity found is similar to that of ddI (EC50 = 4.95 µg mL−1), which is used clinically for the treatment of AIDS patients.

  L-N-MCd4T (1) 作为一种高效的抗HIV药物，从(R)-表氯醇出发，通过串联烷基化、在乳酸酯功能团存在下的酯的选择性还原、环化加成反应和Mitsunobu反应等关键步骤合成，并被发现是一种极为高效的抗HIV-1（EC50 = 6.76 µg mL−1）药物，即使在100 µg mL−1的浓度下也没有细胞毒性，表明其抗HIV-1活性与临床用于治疗AIDS患者的ddI（EC50 = 4.95 µg mL−1）相当。
• Asymmetric Synthesis and Biological Activity of l-Bicyclocarba-d4T
  作者：Hyung Ryong Moon、Ah-Young Park、Kyung Ran Kim、Moon Woo Chun、Lak Shin Jeong

  DOI：10.1080/15257770701615599

  日期：2007.11.26

  Novel L-bicyclocarba-d4T (1), an enantiomer of D-N-MCd4T has been enantiopurely synthesized as a potent anti-HIV agent starting from (R)-epichlorohydrin using tandem alkylation, chemoselective reduction of ester in the presence of lactone functional group, Grignard reaction, RCM reaction, and Mitsunobu reaction as key steps. L-N-MCd4T (1) was found to be very potent anti-HIV-1 (EC50 = 6.76 mu g/mL) agent with no cytotoxicity.
• Understanding How the Herpes Thymidine Kinase Orchestrates Optimal Sugar and Nucleobase Conformations To Accommodate Its Substrate at the Active Site:  A Chemical Approach
  作者：Victor E. Marquez、Yongseok Choi、Maria Julieta Comin、Pamela Russ、Clifford George、Mahmoud Huleihel、Tsipi Ben-Kasus、Riad Agbaria

  DOI：10.1021/ja053789s

  日期：2005.11.1

  The herpes virus thymidine kinase (HSV-tk) is a critical enzyme for the activation of anti-HSV nucleosides. However, a successful therapeutic outcome depends not only on the activity of this enzyme but also on the ability of the compound(s) to interact effectively with cellular kinases and with the target viral or cellular DNA polymerases. Herein, we describe the synthesis and study of two nucleoside analogues built on a conformationally locked bicyclo[3.1.0]hexane template designed to investigate the conformational preferences of HSV-tk for the 2'-deoxyribose ring. Intimately associated with the conformation of the 2'deoxyribose ring is the value of the C-N torsion angle chi, which positions the nucleobase into two different domains (syn or anti). The often-conflicting sugar and nucleobase conformational parameters were studied using North and South methanocarbadeoxythymidine analogues (6 and 7), which forced HSV-tk to make a clear choice in the conformation of the substrate. The results provide new insights into the mechanism of action of this enzyme, which cannot be gleaned from a static X-ray crystal structure.
• Synthesis of enantiomerically pure d- and l-bicyclo[3.1.0]hexenyl carbanucleosides and their antiviral evaluation
  作者：Ah-Young Park、Won Hee Kim、Jin-Ah Kang、Hye Jin Lee、Chong-Kyo Lee、Hyung Ryong Moon

  DOI：10.1016/j.bmc.2011.05.026

  日期：2011.7

  group, a RCM reaction, and a Mitsunobu coupling reaction were used as key reactions. d-Counterpart nucleosides were also prepared according to the same synthetic method. Among the synthesized carbanucleosides, d-thymine nucleoside, d-2 and l-thymine nucleoside, l-2 exhibited excellent anti-HIV-1 and -2 activities, in MT-4 cells, which were higher than those of ddI, an anti-AIDS drug. Whereas d-2 exhibited

  基于已知l-核苷的细胞毒性比d-对应物低的事实，通过采用从 ( R )-表氯醇，以寻找具有高效力和较低细胞毒性的新型抗 HIV 药物。串联烷基化、γ-内酯化、在γ-内酯官能团存在下化学选择性还原酯、RCM反应和Mitsunobu偶联反应被用作关键反应。d-对应的核苷也根据相同的合成方法制备。在合成的碳核苷中， d-胸腺嘧啶核苷、d - 2和l-胸腺嘧啶核苷、l - 2在 MT-4 细胞中表现出优异的抗 HIV-1 和 -2 活性，高于 ddI，一种抗-艾滋病药物。虽然d - 2在 MT-4 细胞系中表现出高细胞毒性，但l - 2在所有测试的细胞系中均未显示出任何可辨别的细胞毒性，这表明l - 2可能是抗艾滋病药物的良好候选者。l -2也显示出弱的抗HSV-2活性而没有细胞毒性。然而，合成的核苷都没有表现出对包括柯萨奇病毒、流感病毒、冠状病毒和脊髓灰质炎病毒在内的 RNA 病毒的抗病毒活性，这可能是由于它们的