谷氨酸,4-亚甲基-,二乙基酯,盐酸 | 139757-98-5

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 中文名称: 谷氨酸,4-亚甲基-,二乙基酯,盐酸
• 英文名称: (+/-)-diethyl-4-methyleneglutamate hydrochloride
• 英文别名: diethyl D,L-4-methyleneglutamate hydrochloride；diethyl-2-amino-4-methylenepentanedionate hydrochloride；Diethyl 2-amino-4-methylidenepentanedioate;hydrochloride
• CAS: 139757-98-5
• 化学式: C₁₀H₁₇NO₄*ClH
• 分子量: 251.71
• InChiKey: UPKZTBQMPKWGTJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.81
• 重原子数：
  16
• 可旋转键数：
  8
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  78.6
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  谷氨酸,4-亚甲基-,二乙基酯,盐酸 在 N-甲基吗啉 、 sodium hydroxide 作用下， 以 乙腈 为溶剂， 反应 36.0h， 生成 2-{4-[2-(2,4-Diamino-pteridin-6-yl)-ethyl]-benzoylamino}-4-methylene-pentanedioic acid
  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-Acetylamino-2-ethoxycarbonyl-4-methylene-pentanedioic acid 1-ethyl ester 5-methyl ester 在 盐酸 、 氯化亚砜 作用下， 以 溶剂黄146 为溶剂， 反应 39.0h， 生成 谷氨酸,4-亚甲基-,二乙基酯,盐酸
  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

• Antifolates for the treatment of cardiovascular, inflammatory, neoplastic, autoimmune and related diseases in sublingual dosage units, film strips, or skin patches
  申请人：Nair Madhavan G.

  公开号：US20100260825A1

  公开（公告）日：2010-10-14

  New metabolism blocked antifolates and their salts are provided along with new indications (coronary heart disease, cardiovascular diseases, stroke and termination of tubal or ectopic pregnancy) and methods (sublingual dosage forms, filmstrips or patches) for their use and delivery. Sublingual dosage forms or trans-dermal patches of metabolically blocked entities of this invention offer superior alternatives to traditional oral dosage forms to achieve greater and predictable therapeutic efficacy, lower toxicity and to overcome drug resistance by virtue of elimination of oxidative deactivation and production of toxic metabolites. Metabolism blocked antifolates bearing a fluorinated benzene ring, a thiophene ring, a pyrrole ring, a furan ring or a 8-deazapteridine ring that are provided in this invention are not previously described. The use of metabolism blocked antifolates to terminate medically complicated pregnancies that are taught herein are new inventions targeted to eliminate drug related toxicity to the host and to enhance therapeutic efficacy.

  本发明提供了新的代谢阻断型抗叶酸剂及其盐，并提供了新的适应症（冠心病、心血管疾病、中风以及输卵管或异位妊娠的终止）和使用方法（舌下剂型、薄膜或贴片）以及其输送方式。本发明中代谢阻断型实体的舌下剂型或经皮贴片，相对于传统的口服剂型，提供了更优越的选择，以实现更大且可预测的治疗效果、更低的毒性，并通过消除氧化失活和产生有毒代谢物来克服药物抵抗。本发明提供的带有氟苯环、噻吩环、吡咯环、呋喃环或8-脱氨嘌呤环的代谢阻断型抗叶酸剂在先前并未描述。本发明中教授的使用代谢阻断型抗叶酸剂来终止医疗复杂的妊娠是新的发明，旨在消除药物相关的对宿主的毒性，并增强治疗效果。
• Nair, M. Gopal; Fayard, Melanie L.; Lariccia, Joanna M., Medicinal Chemistry Research, 1999, vol. 9, # 3, p. 176 - 185
  作者：Nair, M. Gopal、Fayard, Melanie L.、Lariccia, Joanna M.、Amato, Alaina E.、McGuire, John J.、Galivan, John H.、Kisliuk, Roy L.

  DOI：——

  日期：——
• WO2008/89390
  申请人：——

  公开号：——

  公开（公告）日：——
• 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：——
• NEW CLASSICAL ANTIFOLATES
  申请人：Chelsea Therapeutics, Inc.

  公开号：EP2125818A1

  公开（公告）日：2009-12-02