5'-chloromethylphosphonyl-3'-azido-3'-deoxythymidine

• 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: 5'-chloromethylphosphonyl-3'-azido-3'-deoxythymidine
• 英文别名: [(2S,3S,5R)-3-azido-5-(5-methyl-2,4-dioxo-pyrimidin-1-yl)tetrahydrofuran-2-yl]methoxy-(chloromethyl)phosphinic acid；[(2S,3S,5R)-3-azido-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-(chloromethyl)phosphinic acid
• 化学式: C₁₁H₁₅ClN₅O₆P
• 分子量: 379.697
• InChiKey: PDCTYXOYZKEJGU-DJLDLDEBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.1
• 重原子数：
  24
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  120
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  1-[(2R,4S,5S)-4-azido-5-[[chloromethyl(propylamino)phosphoryl]oxymethyl]oxolan-2-yl]-5-methylpyrimidine-2,4-dione 在 吡啶 、 水 作用下， 以 乙腈 为溶剂， 反应 42.0h， 生成 5'-chloromethylphosphonyl-3'-azido-3'-deoxythymidine
  参考文献：
  名称：

  Synthesis and anticancer activity of 5′-chloromethylphosphonates of 3′-azido-3′-deoxythymidine (AZT)

  摘要：

  A series of novel N-alkyl 5'-chloromethylphosphonates of 3'-azido-3'-deoxythymidine (6-15) was synthesized by means of phosphonylation of 3'-azido-3'-deoxythymidine (4) with P-chloromethylphosphonic ditriazolide (3) followed by a reaction with the appropriate amine. The synthesized phosphonamidates 6-15 were evaluated for their cytotoxic activity in two human cancer cell lines: oral (KB) and breast (MCF-7) using the sulforhodamine B (SRB) assay. The highest activity in KB human cancer cells was displayed by phosphonamidate 8 (IC50 = 5.8 mu g/mL), however, this compound was less potent than the parent AZT (IC50 = 3.1 mu g/mL). Phosphonamidate 10 showed only moderate activity (IC50 = 12.1 mu g/mL) whereas the other phosphonamidates proved inactive. Similarly, the highest activity in MCF-7 human cancer cells was displayed by phosphonamidate 8 (IC50 = 3.7 mu g/mL) but it proved somewhat less active than AZT (IC50 = 2.6 mu g/mL). Some activity was also displayed by phosphonamidate 10 (IC50 = 12.8 mu g/mL) but the other phosphonamidates were found inactive. Hydrolysis studies indicate that the synthesized phosphonamidates are likely to act as prodrugs of the parent nucleoside (AZT). Transport measurements showed that the most active phosphonamidates (8 and 10) were able to permeate across the intestinal epithelium in vitro. The apparent permeability coefficients determined in Caco-2 cell monolayers indicated that these compounds could be moderately absorbed in humans. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.08.069