di[5′-O-(3′-azido-2′,3′-dideoxythymidinyl)] 1,4-succinate

• 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: di[5′-O-(3′-azido-2′,3′-dideoxythymidinyl)] 1,4-succinate
• 英文别名: AZT-succinate-AZT；bis[[(2S,3S,5R)-3-azido-5-(5-methyl-2,4-dioxo-pyrimidin-1-yl)tetrahydrofuran-2-yl]methyl] butanedioate；bis[[(2S,3S,5R)-3-azido-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methyl] butanedioate
• 化学式: C₂₄H₂₈N₁₀O₁₀
• 分子量: 616.547
• InChiKey: WIMNKIWFTQCCKN-DWMDIXPDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  44
• 可旋转键数：
  13
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  199
• 氢给体数：
  2
• 氢受体数：
  14

反应信息

• 作为反应物：
  描述：

  di[5′-O-(3′-azido-2′,3′-dideoxythymidinyl)] 1,4-succinate 、 1-[5'-O-(tert-butyldimethylsilyl)-2',3'-dideoxy-β-D-ribofuranosyl]-cytosine 生成 [(2S,3S,5R)-3-azido-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methyl 4-[[1-[(2R,5S)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]oxolan-2-yl]-2-oxopyrimidin-4-yl]amino]-4-oxobutanoate
  参考文献：
  名称：

  TAM, STEVE;WEIGELE, MANFERD;BRODER, SAMUEL;MITSUYA, HIROAKI

  摘要：

  DOI：
• 作为产物：
  描述：

  丁二酸 、 齐多夫定 在 4-二甲氨基吡啶 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 12.0h， 以28%的产率得到di[5′-O-(3′-azido-2′,3′-dideoxythymidinyl)] 1,4-succinate
  参考文献：
  名称：

  Dual inhibitors of the human blood-brain barrier drug efflux transporters P-glycoprotein and ABCG2 based on the antiviral azidothymidine

  摘要：

  The brain provides a sanctuary site for HIV due, in part, to poor penetration of antiretroviral agents at the blood-brain barrier. This lack of penetration is partially attributed to drug efflux transporters such as P-glycoprotein (P-gp) and ABCG2. Inhibition of both ABCG2 and P-gp is critical for enhancing drug accumulation into the brain. In this work, we have developed a class of homodimers based on the HIV reverse transcriptase inhibitor azidothymidine (AZT) that effectively inhibits P-gp and ABCG2. These agents block transporter mediated efflux of the P-gp substrate calcein-AM and the ABCG2 substrate mitoxantrone. The homodimers function by interacting with the transporter drug binding sites as demonstrated by competition studies with the photo-affinity agent and P-gp/ABCG2 substrate [I-125]iodoarylazidoprazosin. As such, these dual inhibitors of both efflux transporters provide a model for the future development of delivery vehicles for antiretroviral agents to the brain. (C) 2017 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2017.07.001

文献信息

• Synthesis and anti-HIV activities of unsymmetrical long chain dicarboxylate esters of dinucleoside reverse transcriptase inhibitors
  作者：Hitesh K. Agarwal、Bhupender S. Chhikara、Gustavo F. Doncel、Keykavous Parang

  DOI：10.1016/j.bmcl.2017.03.031

  日期：2017.5

  dicarboxylic acids, succinic acid, suberic acid and 1,14-tetradecandioc acid, were diesterified with either 3'-azido-2',3'-dideoxythymidine (AZT), 3'-fluoro-2',3'-dideoxythymidine (FLT), 2',3'-dideoxy-3'-thiacytidine (3TC), or 5-fluoro-2',3'-dideoxy-3'-thiacytidine (FTC). The anti-HIV activity of synthesized compounds was evaluated against HIV-1 X4 (IIIB) and R5 (BaL) viral strains in single-round infection

  合成了一系列11种不对称的二核苷逆转录酶抑制剂的二羧酸盐共轭物。用3'-叠氮基2'，3'-二脱氧胸苷（AZT），3'-氟-2'，3'-二脱氧胸苷（3'-叠氮基-2'，3'-二脱氧胸苷（ FLT），2'，3'-二脱氧-3'-硫代胞苷（3TC）或5-氟-2'，3'-二脱氧-3'-硫代胞苷（FTC）。在单轮感染试验中评估了合成化合物对HIV-1 X4（IIIB）和R5（BaL）病毒株的抗HIV活性。结果表明，核苷的十四烷酸酯比相应的母体核苷和核苷结合物具有更强的抗HIV活性。
• TAM, STEVE;WEIGELE, MANFERD;BRODER, SAMUEL;MITSUYA, HIROAKI
  作者：TAM, STEVE、WEIGELE, MANFERD、BRODER, SAMUEL、MITSUYA, HIROAKI

  DOI：——

  日期：——
• Dual inhibitors of the human blood-brain barrier drug efflux transporters P-glycoprotein and ABCG2 based on the antiviral azidothymidine
  作者：Hilda A. Namanja-Magliano、Kelsey Bohn、Neha Agrawal、Meghan E. Willoughby、Christine A. Hrycyna、Jean Chmielewski

  DOI：10.1016/j.bmc.2017.07.001

  日期：2017.10

  The brain provides a sanctuary site for HIV due, in part, to poor penetration of antiretroviral agents at the blood-brain barrier. This lack of penetration is partially attributed to drug efflux transporters such as P-glycoprotein (P-gp) and ABCG2. Inhibition of both ABCG2 and P-gp is critical for enhancing drug accumulation into the brain. In this work, we have developed a class of homodimers based on the HIV reverse transcriptase inhibitor azidothymidine (AZT) that effectively inhibits P-gp and ABCG2. These agents block transporter mediated efflux of the P-gp substrate calcein-AM and the ABCG2 substrate mitoxantrone. The homodimers function by interacting with the transporter drug binding sites as demonstrated by competition studies with the photo-affinity agent and P-gp/ABCG2 substrate [I-125]iodoarylazidoprazosin. As such, these dual inhibitors of both efflux transporters provide a model for the future development of delivery vehicles for antiretroviral agents to the brain. (C) 2017 Elsevier Ltd. All rights reserved.