N-(4-amino-4-deoxy-N¹⁰-methylpteroyl)-4-cyanoglutamic acid | 131215-20-8

• 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: N-(4-amino-4-deoxy-N¹⁰-methylpteroyl)-4-cyanoglutamic acid
• 英文别名: (4S)-2-cyano-4-[[4-[(2,4-diaminopteridin-6-yl)methyl-methylamino]benzoyl]amino]pentanedioic acid
• CAS: 131215-20-8；131215-27-5
• 化学式: C₂₁H₂₁N₉O₅
• 分子量: 479.455
• InChiKey: QTJFCMAGIDQVPI-IAXJKZSUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.9
• 重原子数：
  35
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  234
• 氢给体数：
  5
• 氢受体数：
  13

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 、 二甲基亚砜 为溶剂， 反应 52.0h， 生成 N-(4-amino-4-deoxy-N¹⁰-methylpteroyl)-4-cyanoglutamic 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

• 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.