1-[(1S,2S,5R)-5-(hydroxymethyl)bicyclo[3.1.0]hex-3-en-2-yl]-5-methylpyrimidine-2,4(1H,3H)-dione | 577991-12-9

• 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: 1-[(1S,2S,5R)-5-(hydroxymethyl)bicyclo[3.1.0]hex-3-en-2-yl]-5-methylpyrimidine-2,4(1H,3H)-dione
• 英文别名: 1-[(1S,2S,5R)-5-(hydroxymethyl)-2-bicyclo[3.1.0]hex-3-enyl]-5-methylpyrimidine-2,4-dione
• CAS: 577991-12-9
• 化学式: C₁₂H₁₄N₂O₃
• 分子量: 234.255
• InChiKey: QPYQVQQWMIJOQF-VDDIYKPWSA-N

物化性质

• 熔点：
  181-182 °C
• 密度：
  1.414±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.2
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  69.6
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-[(1S,2S,5R)-5-(hydroxymethyl)bicyclo[3.1.0]hex-3-en-2-yl]-5-methylpyrimidine-2,4(1H,3H)-dione 在 四氮唑 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 1.0h， 生成 (1',2'S,5'R)-5-methyl-1-{5-[(phosphoryloxy)methyl]bicyclo[3.1.0]hex-3-en-2-yl}-1,3-dihydropyrimidine-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
• 作为产物：
  描述：

  N-3-benzoylthymine 在 ammonium hydroxide 作用下， 生成 1-[(1S,2S,5R)-5-(hydroxymethyl)bicyclo[3.1.0]hex-3-en-2-yl]-5-methylpyrimidine-2,4(1H,3H)-dione
  参考文献：
  名称：

  Recent Advances in the Synthesis of Conformationally Locked Nucleosides and Their Success in Probing the Critical Question of Conformational Preferences by Their Biological Targets

  摘要：

  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.

  DOI：

  10.1081/ncn-120021954

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
• 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.
• HALO-DEHYDRO-3'-DEOXYURACIL PHOSPHORAMIDATES AND RELATED COMPOUNDS AND THEIR USE IN TREATING MEDICAL CONDITIONS
  申请人：[en]ROME THERAPEUTICS, INC.

  公开号：WO2024107850A1

  公开（公告）日：2024-05-23

  Substituted halo-dehydro-3'-deoxyuracil phosphoramidates and related compounds, pharmaceutical compositions, their use for inhibiting LINE1 reverse transcriptase and/or HERV-K reverse transcriptase activity, and their use in the treatment of medical disorders, such as cancer, are disclosed herein.
• 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.