2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-4-methylene-pentanedioic acid | 131215-13-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 蝶啶及其衍生物
• 英文名称: 2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-4-methylene-pentanedioic acid
• 英文别名: 2-[[4-[(2,4-diaminopteridin-6-yl)methyl-methylamino]benzoyl]amino]-4-methylidenepentanedioic acid
• CAS: 131215-13-9
• 化学式: C₂₁H₂₂N₈O₅
• 分子量: 466.456
• InChiKey: QOCGFUBRPXAZJX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.3
• 重原子数：
  34
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  211
• 氢给体数：
  5
• 氢受体数：
  12

反应信息

• 作为产物：
  描述：

  4-[N-(2,4-二氨基-6-蝶啶甲基)-N-甲氨基]苯甲酸半盐酸盐n水 在 sodium hydroxide 、 氰基磷酸二乙酯 、 三乙胺 作用下， 以 甲醇 为溶剂， 反应 29.0h， 生成 2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-4-methylene-pentanedioic acid
  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

• Folate analogs. 34. Synthesis and antitumor activity of non-polyglutamylatable inhibitors of dihydrofolate reductase
  作者：Ann Abraham、J. J. McGuire、John Galivan、Zenia Nimec、R. L. Kisliuk、Y. Gaumont、M. G. Nair

  DOI：10.1021/jm00105a035

  日期：1991.1

  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.
• 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：——
• ROSOWSKY, ANDRE;BADER, HENRY;FREISHEIM, JAMES H., J. MED. CHEM., 34,(1991) N, C. 203-208
  作者：ROSOWSKY, ANDRE、BADER, HENRY、FREISHEIM, JAMES H.

  DOI：——

  日期：——
• Analogs of methotrexate and aminopterin with .gamma.-methylene and .gamma.-cyano substitution of the glutamate side chain: synthesis and in vitro biological activity. 40
  作者：Andre Rosowsky、Henry Bader、James H. Freisheim

  DOI：10.1021/jm00105a031

  日期：1991.1

  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.