赖氨酸-甲氨蝶呤 | 80407-56-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 赖氨酸-甲氨蝶呤
• 中文别名: N~2~-(4-{[(2,4-二氨基蝶啶-6-基)甲基](甲基)氨基}苯甲酰)-L-赖氨酸
• 英文名称: N^α-(4-amino-4-deoxy-N¹⁰-methylpteroyl)-L-lysine
• 英文别名: Lysine-methotrexate；(2S)-6-amino-2-[[4-[(2,4-diaminopteridin-6-yl)methyl-methylamino]benzoyl]amino]hexanoic acid
• CAS: 80407-56-3
• 化学式: C₂₁H₂₇N₉O₃
• 分子量: 453.504
• InChiKey: XERJQLWAFDLUGV-HNNXBMFYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -3.9
• 重原子数：
  33
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  199
• 氢给体数：
  5
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  4-硝基苯酚溴乙酯 、 赖氨酸-甲氨蝶呤 在 碳酸氢钠 作用下， 以32.5%的产率得到Sodium; (S)-6-(2-bromo-acetylamino)-2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-hexanoate
  参考文献：
  名称：

  Methotrexate analogs. 30. Dihydrofolate reductase inhibition and in vitro tumor cell growth inhibition by N.epsilon.-(haloacetyl)-L-lysine and N.delta.-(haloacetyl)-L-ornithine analogs and an acivicin analog of methotrexate

  摘要：

  Analogues of methotrexate (MTX) with strong alkylating activity were prepared by replacing the L-glutamate side chain with N omega-haloacetyl derivatives of L-lysine and L-ornithine. Haloacetylation was accomplished in 30-40% yield by reaction of the preformed L-lysine and L-ornithine analogues of MTX with p-nitrophenyl bromoacetate or chloroacetate in aqueous sodium bicarbonate at room temperature. All four haloacetamides were potent inhibitors in spectrophotometric assays measuring noncovalent binding to purified dihydrofolate reductase (DHFR) from L1210 cells. In experiments designed to measure time-dependent inactivation of DHFR from L1210 cells and Candida albicans, the N epsilon-(bromoacetyl)-L-lysine and N delta-(bromoacetyl)-L-ornithine analogues gave results consistent with covalent binding, whereas N epsilon- and N delta-chloroacetyl analogues did not. The N delta-(bromoacetyl)-L-ornithine analogue appeared to be the more reactive one toward both enzymes. Amino acid analysis of acid hydrolysates of the L1210 enzyme following incubation with the bromoacetamides failed to demonstrate the presence of a carboxymethylated residue, suggesting that alkylation had perhaps formed an acid-labile bond. In growth inhibition assays with L1210 cultured murine leukemia cells, the four haloacetamides were all more potent than their nonacylated precursors but less potent than MTX. The greater than 40,000-fold MTX-resistant mutant cell line L1210/R81 was only partly cross-resistant to the haloacetamides. An analogue of MTX with acivicin replacing glutamate was a potent inhibitor of DHFR from chicken liver and L1210 cells but was 200 times less potent than MTX against L1210 cells in culture.

  DOI：

  10.1021/jm00391a031
• 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 N-甲基吗啉 、 三(三氟乙酸)硼烷 、 三氟乙酸 作用下， 以 三氟乙酸 为溶剂， 反应 16.33h， 生成 赖氨酸-甲氨蝶呤
  参考文献：
  名称：

  Lysine and ornithine analogs of methotrexate as inhibitors of dihydrofolate reductase

  摘要：

  The ornithine (6a) and lysine (6b) analogues of methotrexate (1) have been synthesized via condensation of 4-amino-4-deoxy-N10-methylpteroic acid (2) with N gamma-carbobenzoxy-L-ornithine tert-butyl ester (3a) and N epsilon-carbobenzoxy-L-lysine tert-butyl ester (3b), respectively. Removal of the protecting groups gave 5a and 6b. Compounds 6a and 6b and their precursor Cbz acids (5a and 5b) show significant inhibition of dihydrofolate reductase.

  DOI：

  10.1021/jm00346a026

文献信息

• Lysine and ornithine analogs of methotrexate as inhibitors of dihydrofolate reductase
  作者：Robert J. Kempton、Angelique M. Black、Gregory M. Anstead、A. Ashok Kumar、Dale T. Blankenship、James H. Freisheim

  DOI：10.1021/jm00346a026

  日期：1982.4

  The ornithine (6a) and lysine (6b) analogues of methotrexate (1) have been synthesized via condensation of 4-amino-4-deoxy-N10-methylpteroic acid (2) with N gamma-carbobenzoxy-L-ornithine tert-butyl ester (3a) and N epsilon-carbobenzoxy-L-lysine tert-butyl ester (3b), respectively. Removal of the protecting groups gave 5a and 6b. Compounds 6a and 6b and their precursor Cbz acids (5a and 5b) show significant inhibition of dihydrofolate reductase.
• Methotrexate analogs. 15. A methotrexate analogue designed for active-site-directed irreversible inactivation of dihydrofolate reductase
  作者：A. Rosowsky、J. E. Wright、C. Ginty、J. Uren

  DOI：10.1021/jm00350a015

  日期：1982.8

  N alpha-(4-Amino-4-deoxy-N10-methylpteroyl)-N epsilon-(iodoacetyl)-L-lysine (1) was synthesized as a potential active-site-directed irreversible inhibitor of dihydrofolate reductase (DHFR). In an ultraviolet spectrophotometric assay of dihydrofolate reduction of Lactobacillus casei DHFR, 1 and methotrexate (MTX, 4-amino-4-deoxy-N10-methylpteroyl-L-glutamic acid) had ID50 values of 4.5 and 6.2 nM. The corresponding ID50 values in a competitive radioligand binding assay against [3H]MTX were 31 and 16 nM. Thus, as reversible inhibitors of this enzyme over a short exposure time, 1 and MTX had comparable activity. On the other hand, when L. casei DHFR was incubated for up to 6 h with 0.1 or 1.0 microM 1, a progressive decrease in the ability of [3H]MTX to subsequently displace the drug was observed. When MTX itself was used at the same concentrations, the extent of displacement of [3H]MTX did not decrease with time. These results were consistent with rapid reversible binding of 1 to the enzyme, followed more slowly by covalent bond formation near the active site. The pH profile for this effect followed a curve with a sigmoidal shape. The apparent inflection point near pH 7.2 was consistent with alkylation of a histidine residue.
• Synthesis and characterization of a fluorescent analog of methotrexate
  作者：A. Ashok Kumar、James H. Freisheim、Robert J. Kempton、Gregory M. Anstead、Angelique M. Black、Larry Judge

  DOI：10.1021/jm00355a023

  日期：1983.1
• Methotrexate analogs. 30. Dihydrofolate reductase inhibition and in vitro tumor cell growth inhibition by N.epsilon.-(haloacetyl)-L-lysine and N.delta.-(haloacetyl)-L-ornithine analogs and an acivicin analog of methotrexate
  作者：Andre Rosowsky、Vishnu C. Solan、Ronald A. Forsch、Tavner J. Delcamp、David P. Baccanari、James H. Freisheim

  DOI：10.1021/jm00391a031

  日期：1987.8

  Analogues of methotrexate (MTX) with strong alkylating activity were prepared by replacing the L-glutamate side chain with N omega-haloacetyl derivatives of L-lysine and L-ornithine. Haloacetylation was accomplished in 30-40% yield by reaction of the preformed L-lysine and L-ornithine analogues of MTX with p-nitrophenyl bromoacetate or chloroacetate in aqueous sodium bicarbonate at room temperature. All four haloacetamides were potent inhibitors in spectrophotometric assays measuring noncovalent binding to purified dihydrofolate reductase (DHFR) from L1210 cells. In experiments designed to measure time-dependent inactivation of DHFR from L1210 cells and Candida albicans, the N epsilon-(bromoacetyl)-L-lysine and N delta-(bromoacetyl)-L-ornithine analogues gave results consistent with covalent binding, whereas N epsilon- and N delta-chloroacetyl analogues did not. The N delta-(bromoacetyl)-L-ornithine analogue appeared to be the more reactive one toward both enzymes. Amino acid analysis of acid hydrolysates of the L1210 enzyme following incubation with the bromoacetamides failed to demonstrate the presence of a carboxymethylated residue, suggesting that alkylation had perhaps formed an acid-labile bond. In growth inhibition assays with L1210 cultured murine leukemia cells, the four haloacetamides were all more potent than their nonacylated precursors but less potent than MTX. The greater than 40,000-fold MTX-resistant mutant cell line L1210/R81 was only partly cross-resistant to the haloacetamides. An analogue of MTX with acivicin replacing glutamate was a potent inhibitor of DHFR from chicken liver and L1210 cells but was 200 times less potent than MTX against L1210 cells in culture.