amino-N,N-di-(2-bromoethyl)aminophosphoric acid (1,4-naphthoquinone-2-ylmethyl) ester

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: amino-N,N-di-(2-bromoethyl)aminophosphoric acid (1,4-naphthoquinone-2-ylmethyl) ester
• 英文别名: 2-[[Amino-[bis(2-bromoethyl)amino]phosphoryl]oxymethyl]naphthalene-1,4-dione
• 化学式: C₁₅H₁₇Br₂N₂O₄P
• 分子量: 480.093
• InChiKey: ISYZCIXZTRIBDU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  24
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  89.7
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  双(2-溴乙基)胺氢溴酸盐 在 ammonium cerium(IV) nitrate 、 氨 、 三乙胺 、 lithium hexamethyldisilazane 、 三氯氧磷 作用下， 以 四氢呋喃 、 二氯甲烷 、 乙腈 为溶剂， 反应 9.25h， 生成 amino-N,N-di-(2-bromoethyl)aminophosphoric acid (1,4-naphthoquinone-2-ylmethyl) ester
  参考文献：
  名称：

  Development of Novel Quinone Phosphorodiamidate Prodrugs Targeted to DT-Diaphorase

  摘要：

  A series of naphthoquinone and benzimidazolequinone phosphorodiamidates has been synthesized and studied as potential cytotoxic prodrugs activated by DT-diaphorase. Reduction of the quinone moiety in the target compounds was expected to provide a pathway for expulsion of the phosphoramide mustard alkylating agent. All of the compounds synthesized were excellent substrates for purified human DT-diaphorase (k(cat)/K-m = 3 x 10(7) - 3 x 10(8) M-1 s(-1)). The naphthoquinones were toxic to both HT-29 and BE human colon cancer cell lines in a clonogenic assay; however, cytotoxicity did not correlate with DT-diaphorase activity in these cell lines. The benzimidazolequinone analogues were 1-2 orders of magnitude less cytotoxic than the naphthoquinone analogues. Chemical reduction of the naphthoquinone led to rapid expulsion of the phosphorodiamidate anion; in contrast, the benzimidazole reduction product was stable. Michael addition of glutathione and other sulfur nucleophiles provides an alternate mechanism for activation of the naphthoquinone phosphorodiamidates, and this mechanism may contribute to the cytotoxicity of these compounds.

  DOI：

  10.1021/jm000179o

文献信息

• Development of Novel Quinone Phosphorodiamidate Prodrugs Targeted to DT-Diaphorase
  作者：Carolee Flader、Jiwen Liu、Richard F. Borch

  DOI：10.1021/jm000179o

  日期：2000.8.1

  A series of naphthoquinone and benzimidazolequinone phosphorodiamidates has been synthesized and studied as potential cytotoxic prodrugs activated by DT-diaphorase. Reduction of the quinone moiety in the target compounds was expected to provide a pathway for expulsion of the phosphoramide mustard alkylating agent. All of the compounds synthesized were excellent substrates for purified human DT-diaphorase (k(cat)/K-m = 3 x 10(7) - 3 x 10(8) M-1 s(-1)). The naphthoquinones were toxic to both HT-29 and BE human colon cancer cell lines in a clonogenic assay; however, cytotoxicity did not correlate with DT-diaphorase activity in these cell lines. The benzimidazolequinone analogues were 1-2 orders of magnitude less cytotoxic than the naphthoquinone analogues. Chemical reduction of the naphthoquinone led to rapid expulsion of the phosphorodiamidate anion; in contrast, the benzimidazole reduction product was stable. Michael addition of glutathione and other sulfur nucleophiles provides an alternate mechanism for activation of the naphthoquinone phosphorodiamidates, and this mechanism may contribute to the cytotoxicity of these compounds.