5-ethyl 4-acetamido-4-(ethoxycarbonyl)-2-methyleneglutarate | 131216-20-1

• 英文名称: 5-ethyl 4-acetamido-4-(ethoxycarbonyl)-2-methyleneglutarate
• 英文别名: 4-acetamido-5-ethoxy-4-ethoxycarbonyl-2-methylidene-5-oxopentanoic acid
• CAS: 131216-20-1
• 化学式: C₁₃H₁₉NO₇
• 分子量: 301.296
• InChiKey: QOHVNWRJXKOSJJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.02
• 重原子数：
  21.0
• 可旋转键数：
  8.0
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  119.0
• 氢给体数：
  2.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  5-ethyl 4-acetamido-4-(ethoxycarbonyl)-2-methyleneglutarate 在 盐酸 作用下， 以 溶剂黄146 为溶剂， 反应 18.0h， 生成 4-methylene-DL-glutamic acid hydrochloride
  参考文献：
  名称：

  Folate analogs. 34. Synthesis and antitumor activity of non-polyglutamylatable inhibitors of dihydrofolate reductase

  摘要：

  Five analogues of methotrextate (MTX), 10-deazaaminopterin (10-DAM), and 10-ethyl-10-deazaaminopterin (10-EDAM) in which the glutamate moiety was replaced by either a gamma-methyleneglutamate or beta-hydroxyglutamate were synthesized and evaluated for their antifolate activity. These analogous are 4-amino-4-deoxy-N-10-methylpteroyl-beta-hydroxyglutamic acid (1), 4-amino-4-deoxy-10-deazapteroyl-beta-hydroxyglutamic acid (2), 4-amino-4-deoxy-N-10-methylpteroyl-gamma-methyleneglutamic acid (3, MMTX), 4-amino-4-deoxy-10-deazapteroyl-gamma-methyleneglutamic acid (4, MDAM), and 4-amino-4-deoxy-10-ethyl-10-deazapteroyl-gamma-methyleneglutamic acid (5, MEDAM). None of these compounds were metabolized to the respective polyglutamate derivative as judged by their inability to serve as substrates for CCRF-CEM human leukemia cell folypolyglutamate synthetase (FPGS) in vitro. All compounds inhibited recombinant human-dihydrofolate reductase (DHFR) at nearly equivalent magnitude as MTX. Growth-inhibition studies with H35 hepatoma, Manca human lymphoma, and CCRF-CEM human leukemia cells established greater cytotoxic effects with compounds 3-5 than with compounds 1 and 2. Gamma-Methyleneglutamate derivatives 3-5 were transported to H35 hepatoma cells better than MTX or beta-hydroxyglutamate derivatives 1 and 2. Compound 3 was 2.5 times better than MTX in competing with folinic acid transport in H35 hepatoma cells. Compound 1 did not have a significant inhibitory effect on folinic acid transport even at 50-mu-M under identical conditions. The IC50 for compound 1 against H35-hepatoma cell growth was 8.5-fold higher than MTX. Compounds with the gamma-methyleneglutamate moiety (3-5) exhibited almost equal or lower IC50 values than MTX against the growth of CCRF-CEM human leukemia cells. These studies show that on continuous exposure, the non-poly glutamylatable inhibitors DHFR (3-5) can exhibit superior antifolate activity compared to the polyglutamylatable methotrexate, presumably due to their enhanced transport to these cell lines. Compounds 3-5 appear to be excellent models to study the role of polyglutamylation of antifolates in antitumor activity and host toxicity.

  DOI：

  10.1021/jm00105a035
• 作为产物：
  描述：

  2-(溴甲基)丙烯酸 、 乙酰氨基丙二酸二乙酯 在 sodium ethanolate 作用下， 以 乙醇 为溶剂， 以28%的产率得到5-ethyl 4-acetamido-4-(ethoxycarbonyl)-2-methyleneglutarate
  参考文献：
  名称：

  Folate analogs. 34. Synthesis and antitumor activity of non-polyglutamylatable inhibitors of dihydrofolate reductase

  摘要：

  Five analogues of methotrextate (MTX), 10-deazaaminopterin (10-DAM), and 10-ethyl-10-deazaaminopterin (10-EDAM) in which the glutamate moiety was replaced by either a gamma-methyleneglutamate or beta-hydroxyglutamate were synthesized and evaluated for their antifolate activity. These analogous are 4-amino-4-deoxy-N-10-methylpteroyl-beta-hydroxyglutamic acid (1), 4-amino-4-deoxy-10-deazapteroyl-beta-hydroxyglutamic acid (2), 4-amino-4-deoxy-N-10-methylpteroyl-gamma-methyleneglutamic acid (3, MMTX), 4-amino-4-deoxy-10-deazapteroyl-gamma-methyleneglutamic acid (4, MDAM), and 4-amino-4-deoxy-10-ethyl-10-deazapteroyl-gamma-methyleneglutamic acid (5, MEDAM). None of these compounds were metabolized to the respective polyglutamate derivative as judged by their inability to serve as substrates for CCRF-CEM human leukemia cell folypolyglutamate synthetase (FPGS) in vitro. All compounds inhibited recombinant human-dihydrofolate reductase (DHFR) at nearly equivalent magnitude as MTX. Growth-inhibition studies with H35 hepatoma, Manca human lymphoma, and CCRF-CEM human leukemia cells established greater cytotoxic effects with compounds 3-5 than with compounds 1 and 2. Gamma-Methyleneglutamate derivatives 3-5 were transported to H35 hepatoma cells better than MTX or beta-hydroxyglutamate derivatives 1 and 2. Compound 3 was 2.5 times better than MTX in competing with folinic acid transport in H35 hepatoma cells. Compound 1 did not have a significant inhibitory effect on folinic acid transport even at 50-mu-M under identical conditions. The IC50 for compound 1 against H35-hepatoma cell growth was 8.5-fold higher than MTX. Compounds with the gamma-methyleneglutamate moiety (3-5) exhibited almost equal or lower IC50 values than MTX against the growth of CCRF-CEM human leukemia cells. These studies show that on continuous exposure, the non-poly glutamylatable inhibitors DHFR (3-5) can exhibit superior antifolate activity compared to the polyglutamylatable methotrexate, presumably due to their enhanced transport to these cell lines. Compounds 3-5 appear to be excellent models to study the role of polyglutamylation of antifolates in antitumor activity and host toxicity.

  DOI：

  10.1021/jm00105a035

文献信息

• ABRAHAM, ANN;MCGUIRE, J. J.;GALIVAN, JOHN;NIMEC, ZENIA;KISLIUK, R. L.;GAU+, J. MED. CHEM., 34,(1991) N, C. 222-227
  作者：ABRAHAM, ANN、MCGUIRE, J. J.、GALIVAN, JOHN、NIMEC, ZENIA、KISLIUK, R. L.、GAU+

  DOI：——

  日期：——