cyclosaligenyl-2',3'-didehydro-2',3'-dideoxythymidine monophosphate | 188548-79-0

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘧啶核苷酸
• 英文名称: cyclosaligenyl-2',3'-didehydro-2',3'-dideoxythymidine monophosphate
• 英文别名: cycloSal-d4TMP acid；5-H-cycloSal-d4TMP；cycloSal-d4TMP；5-methyl-1-[(2R,5S)-5-[(2-oxo-4H-1,3,2λ5-benzodioxaphosphinin-2-yl)oxymethyl]-2,5-dihydrofuran-2-yl]pyrimidine-2,4-dione
• CAS: 188548-79-0
• 化学式: C₁₇H₁₇N₂O₇P
• 分子量: 392.305
• InChiKey: NEUXRWCLDPVEMR-OHDXJBIGSA-N

物化性质

• 密度：
  1.51±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  27
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  103
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  cyclosaligenyl-2',3'-didehydro-2',3'-dideoxythymidine monophosphate 在 T-lymphocyte CEM cell extracts 作用下， 生成 3'-deoxy-2',3'-didehydro-5'-O-dihydroxyphosphoryl thymidine
  参考文献：
  名称：

  环内Sal-前核苷酸的细胞内捕获：用氨基酸酯修饰前药。

  摘要：

  报道了新型的带有酶可裂解的氨基酸酯的d4TMP-cycloSal-前核苷酸。这些化合物被设计为通过将非极性酯基团快速转变为带电荷的羧酸盐而将原核苷酸捕获在细胞内。这应防止跨细胞膜到细胞外环境的有效扩散平衡，导致化合物在细胞内的积累。该初始转化之后是核苷单磷酸酯（即d4TMP）的缓慢释放。该概念已通过在磷酸盐缓冲液，细胞提取物和人血清中的水解研究得到证明。这些研究表明，某些氨基酸酯修饰对细胞提取物转化的敏感性很高，从而导致带电荷的中间体快速释放，而在磷酸盐缓冲液中没有发现该修饰的切割。此外，还提出了针对艾滋病毒的抗病毒活性。

  DOI：

  10.1021/jm800815b
• 作为产物：
  描述：

  司他夫定 在 叔丁基过氧化氢 、 N,N-二异丙基乙胺 作用下， 以 乙腈 为溶剂， 反应 0.83h， 生成 cyclosaligenyl-2',3'-didehydro-2',3'-dideoxythymidine monophosphate
  参考文献：
  名称：

  cycloSal-2'，3'-dideoxy-2'，3'-didehydrothymidine monophosphate（cycloSal-d4TMP）：新型d4TMP递送系统的合成和抗病毒评估。

  摘要：

  报告了抗HIV双脱氧核苷2'，3'-二脱氧-2'，3'-二脱氢胸苷（d4T，1）的新型亲脂性cycloSal-d4TMP衍生物3a-h的合成，水解和抗病毒评估。该前核苷酸概念已被设计为通过选择性化学水解来递送d4TMP（2）。所有化合物3a-h都是使用磷（III）化学方法合成的，产率很高，而使用磷（V）化学方法则是从取代的水杨醇6a-h开始以较低的产率合成的。相对于在磷中心作为1：1非对映异构体混合物的构型，在没有立体化学偏爱的情况下获得了磷酸三酯3。但是，一些三酯3可以通过半制备HPLC分离为非对映异构体。在1-辛醇/磷酸盐缓冲液混合物中，从其Pa值判断，所有化合物3的亲脂性都比d4T高9-100倍（1）。此外，在水解研究中3在温和的碱性水溶液中分解，仅按照设计的串联反应顺序释放d4TMP（2）和二醇6。观察到由取代基引入的电子性质与三酯3的半衰期的相关性。因此，通过改变取代基，可以在仍

  DOI：

  10.1021/jm970664s

文献信息

• 3,5-Di-(tert-Butyl)-6-fluoro-cycloSal-d4TMP− A Pronucleotide with a Considerably Improved Masking Group
  作者：Christian Ducho、Silke Wendicke、Ulf Görbig、Jan Balzarini、Chris Meier

  DOI：10.1002/ejoc.200300537

  日期：2003.12

  A new, considerably improved cycloSal masking group has been developed. This new group combines four desirable properties and has been attached to the anti-HIV drug 2′,3′-dideoxy-2′,3′-didehydrothymidine (d4T, 1) to give 3,5-(di-tert-butyl)-6-fluoro-cycloSal-d4TMP (2i). This phosphate triester has a reasonable chemical half-life, highly selectively released d4TMP, has poor − if any − inhibitory effect

  已经开发了一种新的、显着改进的 cycloSal 掩蔽组。这个新组结合了四种理想的特性，并已连接到抗 HIV 药物 2',3'-dideoxy-2',3'-didehydrothymidine (d4T, 1) 上以产生 3,5-(di-tert-butyl) -6-氟-环Sal-d4TMP (2i)。这种磷酸三酯具有合理的化学半衰期，高度选择性地释放 d4TMP，对丁酰胆碱酯酶 (BChE) 的抑制作用很差（如果有的话），并实现了 TK 旁路。(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
• Meier, Chris, Angewandte Chemie, 1996, vol. 108, # 1, p. 77 - 79
  作者：Meier, Chris

  DOI：——

  日期：——
• Interaction of <i>cyclo</i>Sal-Pronucleotides with Cholinesterases from Different Origins. A Structure−Activity Relationship
  作者：Chris Meier、Christian Ducho、Ulf Görbig、Robert Esnouf、Jan Balzarini

  DOI：10.1021/jm031032a

  日期：2004.5.1

  A large number of cycloSal-nucleotide triesters 1-49 have been studied concerning their ability to inhibit cholinesterases of different origins as well as to inhibit HIV replication in cell culture. It was shown that none of the triesters showed inhibitory effects against human acetylcholinesterase (AChE; isolated enzyme) as well as against AChE from beef erythrocytes and calf serum. In contrast, inhibition of butyrylcholinesterase (BChE) has been observed for some triesters in human and mouse serum. cycloSal pronucleotides showed strong competitive inhibition with respect to the substrate acetylcholine chloride (K-i/K-m: similar to2 x 10(-5)) and acted by time-dependent irreversible inhibition of the human serum BChE. Detailed studies demonstrated that the inhibitory effect against BChE is dependent on the nucleoside analogue, the substitution pattern of the cycloSal-moiety, and particularly on the stereochemistry at the phosphorus atom. Structural requirements to avoid the inhibition of BChE by cycloSal-nucleotide triesters have been elucidated in the reported study.
• Cyclic saligenyl phosphotriesters of 2′,3′-dideoxy-2′,3′-didehydrothymidine (d4T) — a new pro-nucleotide approach
  作者：Chris Meier、Martina Lorey、E. De Clercq、Jan Balzarini

  DOI：10.1016/s0960-894x(96)00597-5

  日期：1997.1

  The synthesis of a new pro-nucleotide approach for d4TMP 2 based on cycloSal-d4TMP 3a-d is described. Phosphotriesters 3 release d4TMP 2 selectively by a controlled, chemically induced tandem reaction. CycloSal-phosphotriesters 3 exhibited high biological activity against HIV-1/HIV-2 in CEM cells which was retained in CEM TK- cells. (C) 1997, Published by Elsevier Science Ltd.
• <i>Cyclo</i>-saligenyl-2′,3′-dideoxy-2′,3′-didehydroythymidinemonophosphate (<i>cyclo</i>Sal-d4TMP) — A New Pro-Nucleotide Approach
  作者：Chris Meier、Martina Lorey、Eric De Clercq、Jan Balzarini

  DOI：10.1080/07328319708006176

  日期：1997.7

  The synthesis of cycloSal-d4TMP 3a-g as new pro-nucleotide approach for d4TMP 2 is described. Phosphotriesters 3 release the d4TMP 2 selectively by a controlled, chemically induced tandem reaction. CycloSal-phosphotriesters 3 exhibited high biological activity against HIV-1/HIV-2 in CEM cells which was completely retained in CEM TK- cells.