鸟氨酸-甲氨蝶呤 | 80407-73-4

• 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: 鸟氨酸-甲氨蝶呤
• 中文别名: 3-[(2-苯基乙基)氨基]丙氨酸
• 英文名称: N^α-(4-amino-4-deoxy-N¹⁰-methylpteroyl)-L-ornithine
• 英文别名: N^α-(4-amino-4-deoxy-10-methylpteroyl)-L-ornithine；Ornithine-methotrexate；(2S)-5-amino-2-[[4-[(2,4-diaminopteridin-6-yl)methyl-methylamino]benzoyl]amino]pentanoic acid
• CAS: 80407-73-4
• 化学式: C₂₀H₂₅N₉O₃
• 分子量: 439.477
• InChiKey: XZMFYMLGNMSYOG-AWEZNQCLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -4.2
• 重原子数：
  32
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.3
• 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 、 鸟氨酸-甲氨蝶呤 在 碳酸氢钠 作用下， 以34.7%的产率得到Sodium; (S)-5-(2-bromo-acetylamino)-2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-pentanoate
  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 氰基磷酸二乙酯 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 反应 7.0h， 生成 鸟氨酸-甲氨蝶呤
  参考文献：
  名称：

  甲氨蝶呤类似物。26.通过含有碱性氨基酸侧链的甲氨蝶呤和氨基蝶呤类似物抑制二氢叶酸还原酶和叶酰聚谷氨酸合成酶的活性以及体外肿瘤细胞的生长。

  摘要：

  合成了抗肿瘤抗叶酸甲氨蝶呤（MTX）的类似物，其中谷氨酸（Glu）部分被鸟氨酸（Orn），2,4-二氨基丁酸（Dab）或2,3-二氨基丙酸（Dap）代替。还合成了以Orn代替Glu的氨基蝶呤（AMT）类似物。MTX类似物是通过在氨基氰基磷酸二乙酯存在下，使4-氨基-4-脱氧-N10-甲基蝶酸（mAPA）与N-ω-Boc-α，ω-二氨基链烷酸反应，然后用三氟乙酸（TFA）脱保护而获得的。 ）或通过对硝基苯基-mAPA与Nω-Boc-α，ω-二氨基链烷酸反应并随后用TFA处理。AMT类似物（APA-Orn）是通过在55°C下于55°C下使对硝基苯基4-氨基-4-脱氧-N10-甲酰基蝶酸酯与甲硅烷基化的Nδ-Boc-L-鸟氨酸反应3天（产率为45％） ），皂化（83％）和TFA裂解（89％）。APA-Orn是来自L1210小鼠白血病的二氢叶酸还原酶（DHFR）（IC50 = 0.072 micr

  DOI：

  10.1021/jm00155a012

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. 26. Inhibition of dihydrofolate reductase and folylpolyglutamate synthetase activity and in vitro tumor cell growth by methotrexate and aminopterin analogs containing a basic amino acid side chain
  作者：Andre Rosowsky、James H. Freisheim、Richard G. Moran、Vishnu C. Solan、Henry Bader、Joel E. Wright、Mary Radike-Smith

  DOI：10.1021/jm00155a012

  日期：1986.5

  Analogues of the antitumor antifolate methotrexate (MTX) were synthesized in which the glutamate (Glu) moiety was replaced by ornithine (Orn), 2,4-diaminobutyric acid (Dab), or 2,3-diaminopropionic acid (Dap). An aminopterin (AMT) analogue with Orn in place of Glu was also synthesized. The MTX analogues were obtained by reaction of 4-amino-4-deoxy-N10-methylpteroic acid (mAPA) and N omega-Boc-alpha

  合成了抗肿瘤抗叶酸甲氨蝶呤（MTX）的类似物，其中谷氨酸（Glu）部分被鸟氨酸（Orn），2,4-二氨基丁酸（Dab）或2,3-二氨基丙酸（Dap）代替。还合成了以Orn代替Glu的氨基蝶呤（AMT）类似物。MTX类似物是通过在氨基氰基磷酸二乙酯存在下，使4-氨基-4-脱氧-N10-甲基蝶酸（mAPA）与N-ω-Boc-α，ω-二氨基链烷酸反应，然后用三氟乙酸（TFA）脱保护而获得的。 ）或通过对硝基苯基-mAPA与Nω-Boc-α，ω-二氨基链烷酸反应并随后用TFA处理。AMT类似物（APA-Orn）是通过在55°C下于55°C下使对硝基苯基4-氨基-4-脱氧-N10-甲酰基蝶酸酯与甲硅烷基化的Nδ-Boc-L-鸟氨酸反应3天（产率为45％） ），皂化（83％）和TFA裂解（89％）。APA-Orn是来自L1210小鼠白血病的二氢叶酸还原酶（DHFR）（IC50 = 0.072 micr
• 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.