1-[(1S,2S,5R)-5-[[tert-butyl(diphenyl)silyl]oxymethyl]-2-bicyclo[3.1.0]hex-3-enyl]-5-methylpyrimidine-2,4-dione | 577991-20-9

• 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-[(1S,2S,5R)-5-[[tert-butyl(diphenyl)silyl]oxymethyl]-2-bicyclo[3.1.0]hex-3-enyl]-5-methylpyrimidine-2,4-dione
• CAS: 577991-20-9
• 化学式: C₂₈H₃₂N₂O₃Si
• 分子量: 472.659
• InChiKey: QSDPPRNBBVSYDS-FMGHJNRGSA-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-[(1S,2S,5R)-5-[[tert-butyl(diphenyl)silyl]oxymethyl]-2-bicyclo[3.1.0]hex-3-enyl]-5-methylpyrimidine-2,4-dione 在 四氮唑 、 四丁基氟化铵 作用下， 以 四氢呋喃 为溶剂， 反应 1.5h， 生成 (1'S,2'S,5'R)-tert-butyl{[4-(5-methyl-2,4-dioxo-1,3-dihydropyrimidinyl)bicyclo[3.1.0]hex-3-en-2-enyl]methyl}phosphate
  参考文献：
  名称：

  A Conformationally Locked Analogue of the Anti-HIV Agent Stavudine. An Important Correlation between Pseudorotation and Maximum Amplitude

  摘要：

  The synthesis and biological evaluation of a bicyclo[3.1.0]hexene nucleoside designed as a conformational mimic of the anti-HIV agent stavudine (1, D4T) is described. The unsaturated methanocarbocyclic pseudosugar of N-MCD4T (2) was constructed from an iodo-substituted precursor by a DBU-catalyzed olefination reaction. Mitsunobu coupling with N-3-benzoylthymine afforded the desired target after deprotection. Both D4T and N-MCD4T are in the North (N) hemisphere of the pseudorotational cycle but 70degrees away from a perfect N (P = 0degrees) conformation toward the East and West hemispheres, respectively. Despite this large difference, the double bond reduces the puckering amplitude (v(max)) of N-MCD4T to 6.81degrees, and the superposition of both structures showed a RMS deviation of only 0.039 Angstrom. The combined structural analysis of P and vmax shows that while the value of P may differ substantially, the low v(max) resolves the differences and becomes the dominant pseudorotational. parameter. N-MCD4T is active against HIV-1 and HIV-2 in CEM, MT-2, and MT-4 cells, and while it is somewhat less potent than D4T, it also appears to be less toxic. The triphosphate (N-MCD4TTP) inhibits HIV reverse transcriptase with a 10-fold higher IC50 than D4TTP. By virtue of its carbocyclic nature, N-MCD4T (2) is a more robust molecule stable to conditions that would cleave D4T.

  DOI：

  10.1021/jm030116g
• 作为产物：
  描述：

  N-3-benzoylthymine 在 ammonium hydroxide 、 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 4.0h， 生成 1-[(1S,2S,5R)-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：

  A Conformationally Locked Analogue of the Anti-HIV Agent Stavudine. An Important Correlation between Pseudorotation and Maximum Amplitude

  摘要：

  The synthesis and biological evaluation of a bicyclo[3.1.0]hexene nucleoside designed as a conformational mimic of the anti-HIV agent stavudine (1, D4T) is described. The unsaturated methanocarbocyclic pseudosugar of N-MCD4T (2) was constructed from an iodo-substituted precursor by a DBU-catalyzed olefination reaction. Mitsunobu coupling with N-3-benzoylthymine afforded the desired target after deprotection. Both D4T and N-MCD4T are in the North (N) hemisphere of the pseudorotational cycle but 70degrees away from a perfect N (P = 0degrees) conformation toward the East and West hemispheres, respectively. Despite this large difference, the double bond reduces the puckering amplitude (v(max)) of N-MCD4T to 6.81degrees, and the superposition of both structures showed a RMS deviation of only 0.039 Angstrom. The combined structural analysis of P and vmax shows that while the value of P may differ substantially, the low v(max) resolves the differences and becomes the dominant pseudorotational. parameter. N-MCD4T is active against HIV-1 and HIV-2 in CEM, MT-2, and MT-4 cells, and while it is somewhat less potent than D4T, it also appears to be less toxic. The triphosphate (N-MCD4TTP) inhibits HIV reverse transcriptase with a 10-fold higher IC50 than D4TTP. By virtue of its carbocyclic nature, N-MCD4T (2) is a more robust molecule stable to conditions that would cleave D4T.

  DOI：

  10.1021/jm030116g

文献信息

• 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
• Recent Advances in the Synthesis of Conformationally Locked Nucleosides and Their Success in Probing the Critical Question of Conformational Preferences by Their Biological Targets
  作者：Yongseok Choi、Hyung R. Moon、Yuichi Yoshimura、Victor E. Marquez

  DOI：10.1081/ncn-120021954

  日期：2003.10

  The present work describes some recent approaches to the syntheses of three classes of locked-North nucleosides: beta-D-ribo-, beta-D-deoxyribo-, and beta-D-dideoxy-ribonucleosides. The method developed for the latter class permitted access to a novel bicyclo[3.1.0]hexene-type nucleosides structurally similar to D4T and carbovir. A structural analysis and biological activities are discussed.
• A Conformationally Locked Analogue of the Anti-HIV Agent Stavudine. An Important Correlation between Pseudorotation and Maximum Amplitude
  作者：Yongseok Choi、Clifford George、Maria J. Comin、Joseph J. Barchi,、Hak Sung Kim、Kenneth A. Jacobson、Jan Balzarini、Hiroaki Mitsuya、Paul L. Boyer、Stephen H. Hughes、Victor E. Marquez

  DOI：10.1021/jm030116g

  日期：2003.7.1

  The synthesis and biological evaluation of a bicyclo[3.1.0]hexene nucleoside designed as a conformational mimic of the anti-HIV agent stavudine (1, D4T) is described. The unsaturated methanocarbocyclic pseudosugar of N-MCD4T (2) was constructed from an iodo-substituted precursor by a DBU-catalyzed olefination reaction. Mitsunobu coupling with N-3-benzoylthymine afforded the desired target after deprotection. Both D4T and N-MCD4T are in the North (N) hemisphere of the pseudorotational cycle but 70degrees away from a perfect N (P = 0degrees) conformation toward the East and West hemispheres, respectively. Despite this large difference, the double bond reduces the puckering amplitude (v(max)) of N-MCD4T to 6.81degrees, and the superposition of both structures showed a RMS deviation of only 0.039 Angstrom. The combined structural analysis of P and vmax shows that while the value of P may differ substantially, the low v(max) resolves the differences and becomes the dominant pseudorotational. parameter. N-MCD4T is active against HIV-1 and HIV-2 in CEM, MT-2, and MT-4 cells, and while it is somewhat less potent than D4T, it also appears to be less toxic. The triphosphate (N-MCD4TTP) inhibits HIV reverse transcriptase with a 10-fold higher IC50 than D4TTP. By virtue of its carbocyclic nature, N-MCD4T (2) is a more robust molecule stable to conditions that would cleave D4T.