O-isopropyl-O'-(2',3'-didehydro-2',3'-dideoxythymidin-5'-yl) phosphonate | 376357-04-9

• 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: O-isopropyl-O'-(2',3'-didehydro-2',3'-dideoxythymidin-5'-yl) phosphonate
• 英文别名: 2',3'-dideoxy-2',3'-didehydrothymidine 5'-isopropylphosphite；d4T-5'-(O-isopropyl-H-phosphonate)；O-isopropyl-5'-H-phosphonate d4T；5-methyl-1-[(2R,5S)-5-(propan-2-yloxyphosphonoyloxymethyl)-2,5-dihydrofuran-2-yl]pyrimidine-2,4-dione
• CAS: 376357-04-9
• 化学式: C₁₃H₁₉N₂O₆P
• 分子量: 330.277
• InChiKey: IEDIJGNBENFKDH-WDEREUQCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.1
• 重原子数：
  22
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  94.2
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  O-isopropyl-O'-(2',3'-didehydro-2',3'-dideoxythymidin-5'-yl) phosphonate 在 盐酸 、 四氯化碳 、 乙醇 、 氨 、 三乙胺 作用下， 以 四氢呋喃 、 水 、 N,N-二甲基甲酰胺 为溶剂， 生成 N-(3-amino-3-imino-propyl)-4-[[4-[[4-[[isopropoxy-[[(2S,5R)-5-(5-methyl-2,4-dioxo-pyrimidin-1-yl)-2,5-dihydrofuran-2-yl]methoxy]phosphoryl]amino]-1-methyl-pyrrole-2-carbonyl]amino]-1-methyl-pyrrole-2-carbonyl]amino]-1-methyl-pyrrole-2-carboxamide
  参考文献：
  名称：

  Design and synthesis of novel distamycin-modified nucleoside analogues as HIV-1 reverse transcriptase inhibitors

  摘要：

  Design and synthesis of nucleoside analogues have persistently attracted extensive interest because of their potential application in the field of antiviral therapy, and its study also receives additional impetus for improvement in the ProTide technology. Previous studies have made great strides in the design and discovery of monophosphorylated nucleoside analogues as potential kinase-independent antiretrovirals. In this work, a series of nucleoside phosphoramidates modified by distamycin analogues was synthesized and evaluated as nucleoside reverse transcriptase inhibitors (NRTIs) in HIV-1-infected MT-4 and CEM cells, including variations in nucleoside, alkyl moiety, and the structure of distamycin analogues. These compounds exhibited modest potency with the EC50 value in the range of 1.3- to 6.5-fold lower than their corresponding parent drugs in MT-4 cells, which may be attributed to increasing intracellular availability due to the existence of distamycin analogue with favorable hydrophilic-lipophilic equilibrium. Meanwhile, the length of distamycin analogue was considered and assessed as an important factor that could affect antiviral activity and cytotoxicity. Enzymatic and metabolic stability studies have been performed in order to better understand the antiviral behavior of these compounds. The present work revealed the compounds to have a favorable and selective anti-HIV-1 activity in MT-4 and CEM cells, and helped to develop strategies for design and synthesis of effective monophosphorylated nucleoside analogues, which may be applied to antiretroviral research as NRTIs. (C) 2013 Elsevier B.V. All rights reserved.

  DOI：

  10.1016/j.antiviral.2013.12.002
• 作为产物：
  描述：

  司他夫定 在 三氯化磷 作用下， 以 二氯甲烷 为溶剂， 反应 7.5h， 生成 O-isopropyl-O'-(2',3'-didehydro-2',3'-dideoxythymidin-5'-yl) phosphonate
  参考文献：
  名称：

  Novel benzyl rearrangements in electrospray ionization multistage tandem mass spectra of benzyl 2′,3′- didehydro-2′,3′-dideoxythymidin-5′-yl H-phosphonate

  摘要：

  通过电喷雾电离多级串联质谱（ESI-MSn）对几种烷基2′,3′-二脱氢-2′,3′-二脱氧胸苷-5′-基H-磷酸酯进行了合成和分析。在ESI-MS2的[M + H]+、[M + Na]+和[M + K]+中，观察到两种新的苄基重排反应。苄基2′,3′-二脱氢-2′,3′-二脱氧胸苷-5′-基H-磷酸酯的ESI-MS2。串联质谱、高分辨质谱和控制实验的结果表明，苄基迁移可以发生四元环状重排反应，并且苄基在该过程中是必不可少的。版权所有©2004约翰·威利父子有限公司。

  DOI：

  10.1002/jms.643

文献信息

• Selective PP and POP Bond Formations through Copper-Catalyzed Aerobic Oxidative Dehydrogenative Couplings of H-Phosphonates
  作者：Yongbo Zhou、Shuangfeng Yin、Yuxing Gao、Yufen Zhao、Midori Goto、Li-Biao Han

  DOI：10.1002/anie.201003484

  日期：2010.9.10

  Different copper complexes selectively catalyze the aerobic oxidative coupling of H‐phosphonates to afford either hypophosphates and pyrophosphates in high yields with high selectivity (see scheme; tmeda=N,N,N′,N′‐tetramethylethylenediamine).

  不同的铜络合物选择性催化H-膦酸酯的需氧氧化偶联，以高收率和高选择性提供次磷酸盐和焦磷酸盐（参见方案; tmeda = N，N，N'，N'-四甲基乙二胺）。
• Synthesis of AZT/d4T Boranophosphates as Anti-HIV Prodrug Candidates
  作者：Hua Fu、Yufen Zhao、Changxue Lin、Guangzhong Tu

  DOI：10.1055/s-2004-815939

  日期：——

  AZT/d4T phosphonates were synthesized by sequential condensation of AZT/d4T with the corresponding alcohols or 5′-DMT-thymidine in the presence of pivaloyl chloride. Sequential silylation, boronation, and hydrolysis in ammonium hydroxide of these phosphonates led to anti-HIV prodrug candidates AZT/d4T boranophosphates.

  AZT/d4T膦酸盐是通过在异戊酰氯存在下，依次将AZT/d4T与相应的醇或5′-DMT胸苷缩合合成的。这些膦酸盐依次进行硅烷化、硼化及在氨水中水解，得到抗HIV前药候选物AZT/d4T硼膦酸盐。
• Stereospecific Aerobic Oxidative Dehydrocoupling of P(O)–H Bonds with Amines Catalyzed by Copper
  作者：Yongbo Zhou、Jia Yang、Tieqiao Chen、Shuang-Feng Yin、Daoqing Han、Li-Biao Han

  DOI：10.1246/bcsj.20130310

  日期：2014.3.15

  Copper-catalyzed stereospecific oxidative dehydrocouplings of P(O)–H bonds with amines under air took place efficiently at room temperature to afford the corresponding amidophosphorus compounds in high yields. Mechanistic studies showed that this dehydrocoupling reaction proceeded stereospecifically with inversion of stereochemistry at phosphorus.

  在空气中，铜催化的P(O)–H键与胺的立体专一性氧化脱氢偶联反应在室温下高效进行，获得了相应的氨基磷化合物，并且产率很高。机理研究表明，这一脱氢偶联反应以立体专一性的形式进行，伴随磷原子立体化学的反转。
• Gao, Yuxing; Wang, Gang; Chen, Lu, Journal of the American Chemical Society, 2009, vol. 131, p. 7956 - 7957
  作者：Gao, Yuxing、Wang, Gang、Chen, Lu、Xu, Pengxiang、Zhao, Yufen、et al.

  DOI：——

  日期：——
• Novel synthesis and in vitro drug release of polymeric prodrug: Chitosan–O-isopropyl-5′-O-d4T monophosphate conjugate
  作者：Lin Yang、Rong Zeng、Chao Li、Gang Li、Renzhong Qiao、Liming Hu、Zelin Li

  DOI：10.1016/j.bmcl.2009.03.044

  日期：2009.5

  A novel approach to synthesize chitosan-O-isopropyl-5'-O-d4T monophosphate conjugate was developed. Chitosan-d4T monophosphate prodrug with a phosphoramidate linkage was efficiently synthesized through Atherton-Todd reaction. In vitro drug release studies in pH 1.1 and 7.4 indicated that chitosan-O-isopropyl-5'-O-d4T monophosphate conjugate prefers to release the d4T 5'-(O-isopropyl) monophosphate than free d4T for a prolonged period. The results suggested that chitosan-O-isopropyl-5'-O-d4T monophosphate conjugate may be used as a sustained polymeric prodrug for improving therapy efficacy and reducing side effects in antiretroviral treatment. (C) 2009 Elsevier Ltd. All rights reserved.