2-<<2-(dimethylamino)ethoxy>carbonyl>-1-(4-nitrophenyl)ethyl N,N,N',N'-tetrakis(2-chloroethyl)phosphorodiamidate

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 2-<<2-(dimethylamino)ethoxy>carbonyl>-1-(4-nitrophenyl)ethyl N,N,N',N'-tetrakis(2-chloroethyl)phosphorodiamidate
• 英文别名: 2-{[2-(dimethylamino)ethoxy]carbonyl}-1-(4-nitrophenyl)ethyl N,N,N',N'-tetrakis(2-chloroethyl)phosphorodiamidate；2-(Dimethylamino)ethyl 3-[bis[bis(2-chloroethyl)amino]phosphoryloxy]-3-(4-nitrophenyl)propanoate
• 化学式: C₂₁H₃₃Cl₄N₄O₆P
• 分子量: 610.302
• InChiKey: ZIGUFAYGDMCRJK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  36
• 可旋转键数：
  19
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  108
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  2-二甲氨基乙基乙酸酯 在 叔丁基过氧化氢 、 三乙胺 、 lithium hexamethyldisilazane 作用下， 以 异辛烷 、 二氯甲烷 为溶剂， 反应 0.75h， 生成 2-<<2-(dimethylamino)ethoxy>carbonyl>-1-(4-nitrophenyl)ethyl N,N,N',N'-tetrakis(2-chloroethyl)phosphorodiamidate
  参考文献：
  名称：

  Nitrobenzyl Phosphorodiamidates as Potential Hypoxia-Selective Alkylating Agents

  摘要：

  A series of novel nitrobenzyltetrakis(chloroethyl)phosphorodiamidates has been prepared, and its cytotoxicity has been evaluated against HT-29 cells under aerobic and hypoxic conditions and against murine bone marrow progenitor cells under aerobic conditions. All compounds were selectively toxic to HT-29 cells under hypoxic conditions, and the selectivity ratios varied from 1.6 to >90. Analogs lacking either the nitro group or the tetrakis(chloroethyl) moiety were not cytotoxic, confirming that the presence of both nitro and incipient alkylating groups are essential for activity. Surprisingly, some analogs were far more toxic to bone marrow progenitors than to HT-29 cells under aerobic conditions, suggesting that other activation mechanisms must exist in these hematopoietic cells. Cytotoxicity increased with increasing depth in the HT-29 spheroid model, consistent with the preferential hypoxic toxicity of these compounds. Alkaline elution experiments showed a greater number of DNA interstrand cross-links under hypoxic compared to aerobic conditions. The extent of cross-linking in hypoxic cells was essentially identical to that produced by an equitoxic dose of melphalan, suggesting that the cytotoxicity of these compounds results from phosphorodiamidate release and alkylation of DNA.

  DOI：

  10.1021/jm00037a011

文献信息

• Mulcahy R. Timothy, Gipp Jerry J., Schmidt James P., Joswig Carolyn, Borc+, J. Med. Chem, 37 (1994) N 11, S 1610-1615
  作者：Mulcahy R. Timothy, Gipp Jerry J., Schmidt James P., Joswig Carolyn, Borc+

  DOI：——

  日期：——
• Nitrobenzyl Phosphorodiamidates as Potential Hypoxia-Selective Alkylating Agents
  作者：R. Timothy Mulcahy、Jerry J. Gipp、James P. Schmidt、Carolyn Joswig、Richard F. Borch

  DOI：10.1021/jm00037a011

  日期：1994.5

  A series of novel nitrobenzyltetrakis(chloroethyl)phosphorodiamidates has been prepared, and its cytotoxicity has been evaluated against HT-29 cells under aerobic and hypoxic conditions and against murine bone marrow progenitor cells under aerobic conditions. All compounds were selectively toxic to HT-29 cells under hypoxic conditions, and the selectivity ratios varied from 1.6 to >90. Analogs lacking either the nitro group or the tetrakis(chloroethyl) moiety were not cytotoxic, confirming that the presence of both nitro and incipient alkylating groups are essential for activity. Surprisingly, some analogs were far more toxic to bone marrow progenitors than to HT-29 cells under aerobic conditions, suggesting that other activation mechanisms must exist in these hematopoietic cells. Cytotoxicity increased with increasing depth in the HT-29 spheroid model, consistent with the preferential hypoxic toxicity of these compounds. Alkaline elution experiments showed a greater number of DNA interstrand cross-links under hypoxic compared to aerobic conditions. The extent of cross-linking in hypoxic cells was essentially identical to that produced by an equitoxic dose of melphalan, suggesting that the cytotoxicity of these compounds results from phosphorodiamidate release and alkylation of DNA.