4-methylene-DL-glutamic acid hydrochloride | 131235-89-7

• 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
• 英文名称: 4-methylene-DL-glutamic acid hydrochloride
• 英文别名: (+/-)-4-methyleneglutamic acid hydrochloride；(+/-)-2-amino-4-methylene-glutaric acid ; hydrochloride；(+/-)-2-Amino-4-methylen-glutarsaeure; Hydrochlorid；2-Amino-4-methylidenepentanedioic acid hydrochloride；2-amino-4-methylidenepentanedioic acid;hydrochloride
• CAS: 131235-89-7
• 化学式: C₆H₉NO₄*ClH
• 分子量: 195.603
• InChiKey: CTZYRIPUUNZVJK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.15
• 重原子数：
  12
• 可旋转键数：
  4
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  101
• 氢给体数：
  4
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-methylene-DL-glutamic acid hydrochloride 在 N-甲基吗啉 、 氯化亚砜 作用下， 反应 39.0h， 生成
  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：

  diethyl 2-acetamido-2-carbethoxy-4-methyleneglutaric acid 在 盐酸 作用下， 以77%的产率得到4-methylene-DL-glutamic acid hydrochloride
  参考文献：
  名称：

  Analogs of methotrexate and aminopterin with .gamma.-methylene and .gamma.-cyano substitution of the glutamate side chain: synthesis and in vitro biological activity. 40

  摘要：

  Analogues of methotrexate (MTX) and aminopterin (AMT) modified at the gamma-position of the glutamate side chain were synthesized and evaluated as dihydrofolate reductase (DHFR) inhibitors and tumor cell growth inhibitors. Condensations of 4-amino-4-deoxy-N-10-methylpteroic acid (mAPA) with dimethyl DL-4-methyleneglutamate in the presence of diethyl phosphorocyanidate (DEPC) followed by alkaline hydrolysis yielded N-(4-amino-4-deoxy-N-10-methylpteroyl)-DL-4-methyleneglutamic acid (gamma-methyleneMTX). Condensation of 4-amino-4-deoxy-N-10-formylpteroic acid (fAPA) with dimethyl-DL-4-methyleneglutamate by the mixed carboxylic-carbonic anhydride method yielded N-(4-amino-4-deoxypteroyl)-DL-4-methyleneglutamic acid (gamma-methyleneAMT). Also prepared via DEPC coupling was a mixture of the four possible diastereomers of N-(4-amino-4-deoxy-N-10-methylpteroyl)-4-cyanoglutamic acid (gamma-cyanoMTX). The requisite intermediate-gamma-tert-butyl-alpha-methyl 4-cyanoglutamate, as a DL-threo/DL-erythro mixture, was prepared from methyl N-alpha-Boc-O-tosyl-L-serinate by reaction with sodium tert-butyl cyanoacetate followed by mild trifluoroacetic treatment to selectively remove the Boc group. The gamma-methylene derivatives of MTX and AMT are attractive because of their potential to act as Michael acceptors within the DHFR active site. gamma-CyanoMTX may be viewed as a cogener of the nonpolyglutamated MTX analogue-gamma-fluoroMTX. n vitro bioassay data for the gamma-methylene and gamma-cyano compounds support the idea that the active site of DHFR, already known for its ability to tolerate modification of the gamma-carboxyl group of MTX and AMT, can likewise accommodate substitution on the gamma-carbon itself.

  DOI：

  10.1021/jm00105a031

文献信息

• Chemoenzymatic synthesis of optically active α-methylene-γ-carboxy-γ-lactams and γ-lactones
  作者：Annalisa Bertoli、Lidia Fanfoni、Fulvia Felluga、Giuliana Pitacco、Ennio Valentin

  DOI：10.1016/j.tetasy.2009.09.009

  日期：2009.10

  γ-lactones 14 and 15 were synthesised and resolved enzymatically by hydrolysis of their ester function, mediated by commercially available hydrolytic enzymes. In particular, the α-chymotrypsin proved to be active to all the substrates examined, displaying a different degree of activity and enantioselectivity, this latter increasing significantly towards the substrate with an aromatic substituent at the nitrogen

  三个α亚甲基- γ甲酯基γ-butyrolactams（甲基α亚甲基- pyroglutamates）11，12和13，在该杂环中的氮置换不同，以及在结构上相关的γ内酯14和15被合成并通过可商购的水解酶介导的酯功能的水解而被酶解。特别地，事实证明，α-胰凝乳蛋白酶对所有受检底物均具有活性，表现出不同程度的活性和对映选择性，后者朝着在氮原子上带有芳族取代基的底物显着增加。
• Metabolically inert anti-inflammatory and anti-tumor antifolates
  申请人：NAIR, Madhavan G.

  公开号：EP1535911A1

  公开（公告）日：2005-06-01

  The invention relates to a compound according to the general Formula 1e: wherein R is selected from: -NH-, -N(CH3)-.

  本发明涉及通式 1e 的化合物： 其中 R 选自：-NH-、-N(CH3)-。
• 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：——
• METABOLICALLY INERT ANTI-INFLAMMATORY AND ANTI-TUMOR ANTIFOLATES
  申请人：NAIR, Madhavan G.

  公开号：EP1062209A1

  公开（公告）日：2000-12-27
• EP1062209A4
  申请人：——

  公开号：EP1062209A4

  公开（公告）日：2002-02-27