(5-nitrofuran-2-yl)methyl bis(2-bromoethyl)phosphoramidochloridate | 324770-46-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 呋喃
• 英文名称: (5-nitrofuran-2-yl)methyl bis(2-bromoethyl)phosphoramidochloridate
• CAS: 324770-46-9
• 化学式: C₉H₁₂Br₂ClN₂O₅P
• 分子量: 454.439
• InChiKey: KSXPRSNGBOMQFB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.14
• 重原子数：
  20.0
• 可旋转键数：
  9.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  85.82
• 氢给体数：
  0.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  (5-nitrofuran-2-yl)methyl bis(2-bromoethyl)phosphoramidochloridate 在 sodium hydroxide 、 potassium dihydrogenphosphate 、 pig liver esterase 、 18-冠醚-6 、 N,N-二异丙基乙胺 作用下， 以 丙酮 、 乙腈 为溶剂， 反应 39.0h， 生成 (5-nitro-2-furyl)methyl N^ε-lysyl-N,N-bis(2-bromoethyl)phosphorodiamidate
  参考文献：
  名称：

  Synthesis and Evaluation of Pteroic Acid-Conjugated Nitroheterocyclic Phosphoramidates as Folate Receptor-Targeted Alkylating Agents

  摘要：

  A novel nitroheterocyclic bis(haloethyl)phosphoramidate prodrug linked through lysine to a pteroic acid has been prepared and evaluated as a potential alkylating agent, to target tumor cells that overexpress the folate receptor. The prodrug exhibited IC50 values in the micromolar range and was 10-400-fold less cytotoxic in vitro than the phosphoramidate that lacks the lysine-pteroyl moiety. The data does not support a contribution of the folate receptor to cytotoxicity. In an attempt to determine the basis for the decreased cytotoxicity in the pteroyl-lysyl analogue, compounds were prepared in which the lysine-pteroyl moiety was replaced with lysine alone or with an n-propyl group. The n-propyl and the lysyl analogues were on average 3.8- and 21-fold less potent than the unsubstituted bis(haloethyl)phosphoramidate, respectively. Chemical reduction of the prodrugs followed by P-31 NMR kinetics demonstrated that all of the phosphoramidate anions cyclized to the aziridinium ion at similar rates and gave comparable product distributions, suggesting that changes in chemical activation did not account for the differences in cytotoxicity. It, is likely that folate receptor-mediated transport is not sufficient to deliver adequate intracellular concentrations of the cytotoxic phosphoramide mustard.

  DOI：

  10.1021/jm000306g
• 作为产物：
  描述：

  双(2-溴乙基)胺氢溴酸盐 在 三乙胺 、 lithium hexamethyldisilazane 、 三氯氧磷 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 2.88h， 生成 (5-nitrofuran-2-yl)methyl bis(2-bromoethyl)phosphoramidochloridate
  参考文献：
  名称：

  Synthesis and Evaluation of Nitroheterocyclic Phosphoramidates as Hypoxia-Selective Alkylating Agents

  摘要：

  A series of novel nitroheterocyclic phosphoramidates has been prepared, and the cytotoxicity of these compounds has been evaluated in clonogenic assays against B16, wild-type and cyclophosphamide-resistant MCF-7, and HT-29 cells under aerobic conditions and HT-29 cells under hypoxic conditions. All compounds were comparable in toxicity to wild-type and resistant MCF-7 cells and were also selectively toxic to HT-29 cells under hypoxic conditions (selectivity ratios 1.7 to >20). Analogues lacking the nitro group were not cytotoxic. Electron-withdrawing substituents increased cytotoxicity under aerobic conditions and thereby decreased hypoxic selectivity. In contrast, an electron-donating substituent markedly decreased both aerobic and hypoxic cytotoxicity but enhanced hypoxic selectivity. Chemical reduction of the nitro group resulted in rapid expulsion of the cytotoxic phosphoramide mustard. The most potent of these compounds show significant cytotoxicity under both aerobic and hypoxic conditions.

  DOI：

  10.1021/jm0001020

文献信息

• Potent and Highly Selective Hypoxia-Activated Achiral Phosphoramidate Mustards as Anticancer Drugs
  作者：Jian-Xin Duan、Hailong Jiao、Jacob Kaizerman、Timothy Stanton、James W. Evans、Leslie Lan、Gustavo Lorente、Monica Banica、Don Jung、Jinwei Wang、Huaiyu Ma、Xiaoming Li、Zhijian Yang、Robert M. Hoffman、W. Steve Ammons、Charles P. Hart、Mark Matteucci

  DOI：10.1021/jm701028q

  日期：2008.4.1

  A series of achiral hypoxia-activated prodrugs were synthesized on the basis of the DNA cross-linking toxin of the prodrug, ifosfamide. The hypoxia-selective cytotoxicity of several of the compounds was improved over previously reported racemic mixtures of chiral bioreductive phosphorami date prodrugs. Prodrugs activated by 2-nitroimidazole reduction demonstrated up to 400-fold enhanced cytotoxicity toward H460 cells in culture under hypoxia versus their potency under aerobic conditions. Compounds were further assessed for their stability to cytochrome P450 metabolism using a liver microsome assay. The 2-nitroimidazole containing lead compound 3b (TH-302) was selectively potent under hypoxia and stable to liver microsomes. It was active in an in vivo MIA PaCa-2 pancreatic cancer orthotopic xenograft model as a monotherapy and demonstrated dramatic efficacy when used in combination with gemcitabine, extending survival with one of eight animals tumor free at day-44. Compound 3b has emerged as a promising antitumor agent that shows excellent in vivo efficacy and is currently being evaluated in the clinic.