alaninyl-d4T-monophosphate | 180076-92-0

• 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: alaninyl-d4T-monophosphate
• 英文别名: (2S)-2-[[hydroxy-[[(2S,5R)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)-2,5-dihydrofuran-2-yl]methoxy]phosphoryl]amino]propanoic acid
• CAS: 180076-92-0
• 化学式: C₁₃H₁₈N₃O₈P
• 分子量: 375.275
• InChiKey: LEWGXEFLCSVQEP-LPEHRKFASA-N

物化性质

• 密度：
  1.519±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -1.7
• 重原子数：
  25
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  155
• 氢给体数：
  4
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  司他夫定 在 N-甲基咪唑 、 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 7.0h， 生成 alaninyl-d4T-monophosphate
  参考文献：
  名称：

  Aryl Phosphoramidate Derivatives of d4T Have Improved Anti-HIV Efficacy in Tissue Culture and May Act by the Generation of a Novel Intracellular Metabolite

  摘要：

  New phosphate derivatives of the anti-HIV nucleoside analogue d4T were prepared as potential membrane-soluble prodrugs of the bioactive free nucleotide. The enhanced antiviral potency and/or reduced cytotoxicity of the derivatives leads to an increase in selectivity relative to the parent nucleoside analogue. Moreover, the derivatives appear to bypass the dependence of the nucleoside on thymidine kinase-mediated activation, retaining full activity in thymidine kinase-deficient cells. This strongly suggests the successful intracellular delivery of free nucleotides by the masked phosphate triester prodrugs. This is further confirmed by studies using radiolabeled compound which clearly demonstrate the generation of d4T mono-, di- and triphosphates from the prodrug, even in thymidine kinase-deficient cells. Moreover, we herein report the generation of a new metabolite, a partially hydrolyzed phosphate diester, alaninyl d4T monophosphate. We suggest that at least part of the antiviral action of the prodrugs derives from the intracellular generation of such novel diesters which may add considerable weight to the suggested further preclinical development of the phosphate prodrugs.

  DOI：

  10.1021/jm950605j

文献信息

• Protease-mediated enzymatic hydrolysis and activation of aryl phosphoramidate derivatives of stavudine
  作者：T.K. Venkatachalam、P. Samuel、S. Qazi、F.M. Uckun

  DOI：10.1016/j.ejmech.2004.11.015

  日期：2005.5

  several protease inhibitors to block the hydrolysis of these phosphoramidate derivatives. We found that these proteases exhibit chiral selectivity at the phosphorus center of stavudine derivatives. Our results indicate that cellular proteases may be responsible for the activation of these phosphoramidate derivatives. In addition, we show that the enzymatic hydrolysis takes place at the carboxymethyl ester

  几种蛋白酶能够水解司他夫定的芳基取代的氨基磷酸酯衍生物，从而形成活性代谢产物丙氨酰基d4T单磷酸酯。枯草蛋白酶蛋白酶A，枯草杆菌蛋白酶Griseus，枯草杆菌蛋白酶Carlsberg，木瓜，芽孢杆菌是水解司他夫定衍生物的最有效蛋白酶之一，并且使用几种蛋白酶抑制剂来阻断这些氨基磷酸酯衍生物的水解已证实了其活性的特异性。我们发现这些蛋白酶在司他夫定衍生物的磷中心具有手性选择性。我们的结果表明，细胞蛋白酶可能负责这些氨基磷酸酯衍生物的活化。此外，我们表明，酶促水解发生在这些前药的羧甲基酯侧链上，并且不会发生这些酶对磷中心的直接攻击。最后，我们描述了迄今未知的司他夫定的这些氨基磷酸酯衍生物的活化和病毒抑制特性的新型活化途径。
• In Vivo Toxicity, Pharmacokinetics, and Anti-Human Immunodeficiency Virus Activity of Stavudine-5′-(<i>p</i>-Bromophenyl Methoxyalaninyl Phosphate) (Stampidine) in Mice
  作者：Fatih M. Uckun、Sanjive Qazi、Sharon Pendergrass、Elizabeth Lisowski、Barbara Waurzyniak、Chun-Lin Chen、T. K. Venkatachalam

  DOI：10.1128/aac.46.11.3428-3436.2002

  日期：2002.11

  We have evaluated the clinical potential of stavudine-5′-(p-bromophenyl methoxyalaninyl phosphate(stampidine [STAMP]), a novel aryl phosphate derivative of stavudine, as a new anti-human immunodeficiency virus (anti-HIV) agent, by examining its acute, subacute, and chronic toxicity profile in mice as well as by testing its antiviral activity in a surrogate human peripheral blood lymphocyte (Hu-PBL)-SCID mouse model of human AIDS. STAMP was very well tolerated in BALB/c and CD-1 mice, without any detectable acute or subacute toxicity at single intraperitoneal or oral bolus doses as high as 500 mg/kg of body weight. Notably, daily administration of STAMP intraperitoneally or orally for up to 8 consecutive weeks was not associated with any detectable toxicity at cumulative dose levels as high as 6.4 g/kg. Micromolar concentrations of the active STAMP metabolite in plasma were rapidly achieved and maintained for more than 4 h after parenteral as well as oral administration of a nontoxic 100-mg/kg bolus dose of STAMP. In accordance with its favorable pharmacokinetic profile and in vitro potency, STAMP exhibited dose-dependent and potent in vivo anti-HIV activity in Hu-PBL-SCID mice against a genotypically and phenotypically nucleoside analog reverse transcriptase inhibitor (NRTI)-resistant clinical HIV type 1 (HIV-1) isolate (BR/92/019; D67N, L214F, T215D, K219Q) at nontoxic dose levels. The remarkable in vivo safety and potency of STAMP warrants the further development of this promising new antiretroviral agent for possible clinical use in patients harboring NRTI-resistant HIV-1.

  摘要 我们评估了司他夫定-5′-(对溴苯甲氧基丙氨酰磷酸酯(STAMP))作为一种新型抗人类免疫缺陷病毒（抗 HIV）药物的临床潜力，它是司他夫定的一种新型芳基磷酸酯衍生物、通过研究其在小鼠体内的急性、亚急性和慢性毒性概况，以及在人类艾滋病的代用人类外周血淋巴细胞（Hu-PBL）-SCID 小鼠模型中测试其抗病毒活性。BALB/c 和 CD-1 小鼠对 STAMP 的耐受性非常好，单次腹腔注射或口服剂量高达 500 毫克/千克体重时，均未检测到任何急性或亚急性毒性。值得注意的是，连续 8 周每天腹腔注射或口服 STAMP，在累积剂量高达 6.4 克/千克时也未检测到任何毒性。肠外和口服 100 毫克/千克无毒剂量的 STAMP 后，血浆中 STAMP 活性代谢物的微摩尔浓度可迅速达到并维持 4 小时以上。根据其良好的药代动力学特征和体外效力，STAMP 在 Hu-PBL-SCID 小鼠体内对基因型和表型上具有核苷类似物逆转录酶抑制剂（NRTI）抗性的临床 HIV 1 型（HIV-1）分离株（BR/92/019；D67N、L214F、T215D、K219Q）在无毒剂量水平上表现出剂量依赖性和强效的抗 HIV 活性。STAMP 显着的体内安全性和药效使我们有理由进一步开发这种前景广阔的新型抗逆转录病毒药物，以便在临床上用于对 NRTI 耐药的 HIV-1 患者。
• Aryl Phosphoramidate Derivatives of d4T Have Improved Anti-HIV Efficacy in Tissue Culture and May Act by the Generation of a Novel Intracellular Metabolite
  作者：Christopher McGuigan、Dominique Cahard、Hendrika M. Sheeka、Erik De Clercq、Jan Balzarini

  DOI：10.1021/jm950605j

  日期：1996.1.1

  New phosphate derivatives of the anti-HIV nucleoside analogue d4T were prepared as potential membrane-soluble prodrugs of the bioactive free nucleotide. The enhanced antiviral potency and/or reduced cytotoxicity of the derivatives leads to an increase in selectivity relative to the parent nucleoside analogue. Moreover, the derivatives appear to bypass the dependence of the nucleoside on thymidine kinase-mediated activation, retaining full activity in thymidine kinase-deficient cells. This strongly suggests the successful intracellular delivery of free nucleotides by the masked phosphate triester prodrugs. This is further confirmed by studies using radiolabeled compound which clearly demonstrate the generation of d4T mono-, di- and triphosphates from the prodrug, even in thymidine kinase-deficient cells. Moreover, we herein report the generation of a new metabolite, a partially hydrolyzed phosphate diester, alaninyl d4T monophosphate. We suggest that at least part of the antiviral action of the prodrugs derives from the intracellular generation of such novel diesters which may add considerable weight to the suggested further preclinical development of the phosphate prodrugs.