3'-azido-3'-deoxythymidine 5'-hemiglutarate | 128305-54-4

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘧啶核苷
• 英文名称: 3'-azido-3'-deoxythymidine 5'-hemiglutarate
• 英文别名: mono-(3'-azido-3'-deoxythymidin-5'-yl) ester 1,5-pentanedioic acid；3'-acido-3'-deoxy-5'-O-glutarylthymidine acid；5-((3-azido-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methoxy)-5-oxopentanoic acid；5-((3-azido-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidine-1(2H)-yl)tetrahydrofuran-2-yl)methoxy)-5-oxovaleric acid；5-[[(2S,3S,5R)-3-azido-5-(5-methyl-2,4-dioxo-pyrimidin-1-yl)tetrahydrofuran-2-yl]methoxy]-5-oxo-pentanoic acid；5-[[(2S,3S,5R)-3-azido-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy]-5-oxopentanoic acid
• CAS: 128305-54-4
• 化学式: C₁₅H₁₉N₅O₇
• 分子量: 381.345
• InChiKey: AICHWAOJFIZLTA-HBNTYKKESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  27
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  137
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  3'-azido-3'-deoxythymidine 5'-hemiglutarate 在 4-二甲氨基吡啶 、 三乙胺 作用下， 以 二氯甲烷 、 乙酸乙酯 为溶剂， 反应 18.0h， 生成 1-(3'-azido-3'-deoxythymidin-5'-yl), 5-(tert-butyl) pentanedioate
  参考文献：
  名称：

  New 3‘-Azido-3‘-deoxythymidin-5‘-yl O-(ω-Hydroxyalkyl) Carbonate Prodrugs:  Synthesis and Anti-HIV Evaluation

  摘要：

  Prodrugs of zidovudine (AZT) have been synthesized in an effort to enhance its uptake by HIV-1 infected cells and its anti-HIV activity. The 5'-OH function of AZT was functionalized with various enzymatically labile alkyl groups using specific procedures. The prodrug moieties included 5'-O-carbonate, 5'-O-carbamate, and 5'-O-ester. Analogues of the 3'-azido-3'-deoxy-thymidin-5'-yl O-(omega -hydroxyalkyl) carbonate series were particularly interesting since they were rearranged through an intramolecular cyclic process during their enzymatic hydrolysis. Evidence of this prodrug rearrangement was confirmed by comparison of the serum half-lives of 5'-O-carbonate prodrugs with their corresponding 5'-O-ester- and 5'-O-carbamate-AZT prodrugs. Interestingly, the anti-HIV-1 activities (EC50) of 3'-azido-3'-deoxythymidin-5'-yl O-(4-hydroxybutyl) carbonate 10 in acutely infected MT-4 cells and in peripheral blood mononuclear cells (PBMCs) were 0.5 nM and 0.78 nM, respectively. Compound 10 was 30 to 50 times more potent than its parent drug AZT. Our results suggest that the specific intramolecular rearrangement associated with the 3'-azido-3'-deoxythymidin-5'-yl O-(omega -hydroxyalkyl) carbonate prodrugs could explain the remarkable anti-HIV-1 activity of this series of AZT prodrugs. Prodrug 10 may therefore have better clinical potential than AZT for the treatment of AIDS.

  DOI：

  10.1021/jm001033s
• 作为产物：
  描述：

  戊二酸 、 齐多夫定 在 4-二甲氨基吡啶 、 N,N'-二环己基碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 反应 72.25h， 以60%的产率得到3'-azido-3'-deoxythymidine 5'-hemiglutarate
  参考文献：
  名称：

  具有最佳化学稳定性的AZT前药的评估和合成：实验和理论分析†

  摘要：

  核苷逆转录酶抑制剂（NRTIs）的前药设计构成了一种有前途的策略，可以克服这些药物的几种次优药物治疗特性，其中齐多夫定（AZT）是研究最多的例子。在药物治疗性能的背景下，前药的化学稳定性是一个关键问题，因为它是生物活性NRTIs转化的关键事件。在这项研究中，通过DFT和经典分子动力学（MD）策略研究了AZT和拉米夫定（3TC）的5种前药，以模拟涉及其化学水解的反应坐标，并将这些结论扩展到前药的进一步结构合理化。所以，发现包含明确的水分子与提到的反应坐标非常相关，因为它允许计算出的反应能量值和相应的水解常数之间非常良好的相关性。基于这些发现，设计，合成和评估了三种基于AZT的酯基前药。与先前报道的AZT前药相比，这些前药表现出优化的化学稳定性，这可能导致增强的药物治疗性能。总之，建立的理论模型为具有合理化学稳定性的NTRI新型前药的设计和开发提供了宝贵的帮助。

  DOI：

  10.1039/c5nj03002a

文献信息

• Discovery of potential dual-target prodrugs of HIV-1 reverse transcriptase and nucleocapsid protein 7
  作者：Songkai Sun、Boshi Huang、Zhuo Li、Zhao Wang、Lin Sun、Ping Gao、Dongwei Kang、Chin-Ho Chen、Kuo-Hsiung Lee、Dirk Daelemans、Erik De Clercq、Christophe Pannecouque、Peng Zhan、Xinyong Liu

  DOI：10.1016/j.bmcl.2020.127287

  日期：2020.8

  In the present work, we described the design, synthesis and biological evaluation of a novel series of potential dual-target prodrugs targeting the HIV-1 reverse transcriptase (RT) and nucleocapsid protein 7 (NCp7) simultaneously. Among them, the most effective compound 7c was found to inhibit HIV-1 wild-type (WT) strain at double-digit nanomolar concentration (EC50 = 42 nM) in MT-4 cells, and sub-micromole

  在本工作中，我们描述了同时靶向HIV-1逆转录酶（RT）和核衣壳蛋白7（NCp7）的一系列潜在的双靶标前药的设计，合成和生物学评估。其中，发现最有效的化合物7c 在MT-4细胞中以两位数纳摩尔浓度（EC 50 = 42 nM）和亚微摩尔（EC 50  = 0.308 ）抑制HIV-1野生型（WT）菌株。（μM）抑制TZM-bl细胞中的HIV-1 NL4-3株。这是对母体药物MT的重大改进。此外，它对 HIV-1 K103N / Y181C双突变株（MT-4细胞）显示出中等抑制力（EC 50 = 1.329μM）。化合物7c在人血浆中的代谢稳定性 指出它可以以线性时间独立的方式释放母体药物MT和AZT的活性形式，并证明是潜在的前药。
• Convenient one-pot synthesis of cystine-containing peptides using the trimethylsilyl chloride–dimethyl sulfoxide/trifluoroacetic acid system and its application to the synthesis of bifunctional anti-HIV compounds 1
  作者：Hirokazu Tamamura、Tsunehito Ishihara、Hiromi Oyake、Makoto Imai、Akira Otaka、Toshiro Ibuka、Rieko Arakaki、Hideki Nakashima、Tsutomu Murakami、Michinori Waki、Akiyoshi Matsumoto、Naoki Yamamoto、Nobutaka Fujii

  DOI：10.1039/a706545k

  日期：——

  A one-pot synthesis of cystine-containing peptides is achieved by treatment of protected peptidyl resins with trimethylsilyl chloride–dimethyl sulfoxide/trifluoroacetic acid in the presence of anisole. This methodology has been successfully applied to the synthesis of highly active anti-HIV peptides conjugated with 3′-azido-3′-deoxythymidine.

  在苯甲醚存在的情况下，用三甲基氯硅烷-二甲基亚砜/三氟乙酸处理受保护的肽基树脂，实现了含胱氨酸肽的一步法合成。这种方法已成功应用于合成与 3â²-叠氮-3â²-脱氧胸苷共轭的高活性抗艾滋病毒肽。
• Synthesis of New Homo and Heterodimers of 2′,3′-Dideoxyinosine (ddi) Using Ester Linkages
  作者：L. Ait Mohamed、M. Taourirte、A. Rochdi、H. B. Lazrek、J. J. Vasseur、J. W. Engels、C. Pannecouque、E. De Clercq

  DOI：10.1081/ncn-120022664

  日期：2003.10

  A series of new homo and heterodimers of ddI has been synthesized. A glutarate diester spacer was used to covalently couple ddI onto ddI, AZT or d4T.
• [EN] HYBRID MOLECULES OF MACROLIDES WITH STEROID/NON-STEROID ANTI-INFLAMMATORY, ANTINEOPLASTIC AND ANTIVIRAL ACTIVE MOLECULES<br/>[FR] NOUVEAUX COMPOSES, COMPOSITIONS EN TANT QUE PORTEURS POUR MOLECULES ACTIVES ANTI-INFLAMMATOIRES STEROIDIENNES/NON-STEROIDIENNES, ANTINEOPLASIQUES ET ANTIVIRALES
  申请人：PLIVA ISTRAZIVACKI INST D O O

  公开号：WO2004005313A3

  公开（公告）日：2005-04-21
• Optimization of Antiviral Prodrug Properties Using Combinatorial Methods
  作者：Yulia V. Berezovskaya、Mikhail V. Chudinov、Alexander M. Yurkevich

  DOI：10.1081/ncn-120022666

  日期：2003.10

  Some diacid biodegradable synthesis of aziduthymidine (AZT) were synthesized and applied to production of about 60 different derivatives.