甲氨蝶呤杂质 | 73610-81-8

• 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
• 中文名称: 甲氨蝶呤杂质
• 英文名称: N-methylamino>benzoyl>-L-γ-glutamyl>-L-γ-glutamyl>-L-γ-glutamyl>-L-γ-glutamic acid
• 英文别名: 4-amino-4-deoxy-N¹⁰-methylpteroyltetraglutamate；4-NH2-10-CH3-folyltetraglutamate；MTX tetraglutamate；methotrexate tetraglutamate；L-Glutamic acid, N-(N-(N-(N-(4-(((2,4-diamino-6-pteridinyl)methyl)-methylamino)benzoyl)-L-gamma-glutamyl)-L-gamma-glutamyl)-L-gamma-glutamyl)-；(2S)-2-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[4-[(2,4-diaminopteridin-6-yl)methyl-methylamino]benzoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]amino]pentanedioic acid
• CAS: 73610-81-8
• 化学式: C₃₅H₄₃N₁₁O₁₄
• 分子量: 841.792
• InChiKey: UORBZCNWEGKEOP-CMOCDZPBSA-N

物化性质

• 熔点：
  >123°C (dec.)
• 密度：
  1.541±0.06 g/cm3(Predicted)
• 溶解度：
  DMSO（微溶）、甲醇（微溶）

计算性质

• 辛醇/水分配系数(LogP)：
  -4.1
• 重原子数：
  60
• 可旋转键数：
  24
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  410
• 氢给体数：
  11
• 氢受体数：
  21

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 哌啶 、 N-甲基吗啉 、 盐酸 、 4-二甲氨基吡啶 、 KH poliamide resin 、 三氟乙酸 作用下， 以 四氢呋喃 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 48.0h， 生成 甲氨蝶呤杂质
  参考文献：
  名称：

  Folate analogs. 33. Synthesis of folate and antifolate poly-.gamma.-glutamates by [(9-fluorenylmethoxy)oxy]carbonyl chemistry and biological evaluation of certain methotrexate polyglutamate polylysine conjugates as inhibitors of the growth of H35 hepatoma cells

  摘要：

  Representative examples of folate and antifolate poly-gamma-glutamyl metabolites were synthesized via the [(9-fluorenylmethoxy)oxy]carbonyl (Fmoc) chemistry using the KH polyamide resin. Polyglutamate yields were consistently better in all cases compared to the previous Merrifield method, and the crude products were obtained in greater than 85% purity. The symmetrical anhydride (7) derived from alpha-tert-butyl N-Fmoc-L-glutamate (6) was used for the initial coupling of the first glutamate residue to the KH resin and also for subsequent chain elongation. The alpha-tert-butyl protective groups were not labile under the conditions used for the cleavage of the finished peptide from the resin. A series of poly-gamma-glutamyl metabolites of methotrexate (MTX) with a chain length ranging from two to five glutamyl residues were synthesized and coupled with poly(L-lysine) having an average molecular weight of 27,000 and 52,000. Each conjugate was tested for its ability to inhibit the growth of wild type (H35) and MTX transport resistant (H35R) strains of hepatoma cells in culture, the latter having a 100-fold reduced sensitivity to MTX. 4-Amino-4-deoxy-N10-methylpteroylglutamyl-gamma-glutamylpoly (L-lysine) conjugate [MTX(G2)-poly-L-Lys-52000] and MTX(G4)-poly-L-Lys-52000 were among the most active (I50 = 8.0 and 10 nM against H35 cells) MTX-polylysines synthesized to date, and they were somewhat more inhibitory to the transport resistant cells. MTX(G5)-poly-L-Lys-52000 was approximately 1000 times more effective than MTX(G5)-poly-D-Lys-52000 in inhibiting the growth of H35R hepatoma cells in culture, indicating that internal cleavage of the gamma-glutamate chain of the conjugate with subsequent release of MTX or shorter chain polyglutamates of MTX is unlikely to be an important determinant of MTX-polyglutamate polylysine cytotoxicity. The results indicate that MTX-polyglutamate poly(L-lysine) conjugates are taken up by the cells independently of MTX and probably via endocytosis.

  DOI：

  10.1021/jm00164a038

文献信息

• A synthetic approach to poly(.gamma.-glutamyl) conjugates of methotrexate
  作者：James R. Piper、George S. McCaleb、John A. Montgomery

  DOI：10.1021/jm00356a035

  日期：1983.2

  one added glutamate unit. Key steps in the sequence are the peptide coupling of N-[4-[[(benzyloxy)carbonyl]-methylamino]benzoyl]-L-glutamic acid alpha-benzyl ester (5) with oligo(gamma-L-glutamate) benzyl esters, removal of blocking groups by catalytic hydrogenolysis, and introduction of the (2,4-diamino-6-pteridinyl)methyl grouping by alkylation with 6-(bromomethyl)-2,4-pteridinediamine hydrobromide

  甲氨蝶呤聚（γ-L-谷氨酸）比甲氨蝶呤中存在的谷氨酸单元高两个和三个，这是通过扩展前述合成具有一个添加的谷氨酸单元的较低缀合物的路线的合成而合成的。序列中的关键步骤是N- [4-[[（（苄氧基）羰基]-甲基氨基]苯甲酰基] -L-谷氨酸α-苄基酯（5）与低聚（γ-L-谷氨酸）苄基酯的肽偶联，通过催化氢解作用除去保护基团，以及通过用6-（溴甲基）-2,4-哌啶二胺氢溴酸盐进行烷基化来引入（2,4-二氨基-6-哌啶基）甲基。从L-谷氨酸二苄基酯与[（叔丁氧基）羰基] -L-谷氨酸α-苄基酯的偶联开始，一次精制所需的寡（γ-L-谷氨酸）链。 （7），然后选择性地除去叔丁氧羰基，并根据需要进行另一个偶联步骤（5或7）。在每次产生肽键的转化中，将二苯基磷酰基叠氮化物用作偶联剂。
• Folate analogs. 33. Synthesis of folate and antifolate poly-.gamma.-glutamates by [(9-fluorenylmethoxy)oxy]carbonyl chemistry and biological evaluation of certain methotrexate polyglutamate polylysine conjugates as inhibitors of the growth of H35 hepatoma cells
  作者：Ann Abraham、M. G. Nair、R. L. Kisliuk、J. Galivan、Y. Gaumont

  DOI：10.1021/jm00164a038

  日期：1990.2

  Representative examples of folate and antifolate poly-gamma-glutamyl metabolites were synthesized via the [(9-fluorenylmethoxy)oxy]carbonyl (Fmoc) chemistry using the KH polyamide resin. Polyglutamate yields were consistently better in all cases compared to the previous Merrifield method, and the crude products were obtained in greater than 85% purity. The symmetrical anhydride (7) derived from alpha-tert-butyl N-Fmoc-L-glutamate (6) was used for the initial coupling of the first glutamate residue to the KH resin and also for subsequent chain elongation. The alpha-tert-butyl protective groups were not labile under the conditions used for the cleavage of the finished peptide from the resin. A series of poly-gamma-glutamyl metabolites of methotrexate (MTX) with a chain length ranging from two to five glutamyl residues were synthesized and coupled with poly(L-lysine) having an average molecular weight of 27,000 and 52,000. Each conjugate was tested for its ability to inhibit the growth of wild type (H35) and MTX transport resistant (H35R) strains of hepatoma cells in culture, the latter having a 100-fold reduced sensitivity to MTX. 4-Amino-4-deoxy-N10-methylpteroylglutamyl-gamma-glutamylpoly (L-lysine) conjugate [MTX(G2)-poly-L-Lys-52000] and MTX(G4)-poly-L-Lys-52000 were among the most active (I50 = 8.0 and 10 nM against H35 cells) MTX-polylysines synthesized to date, and they were somewhat more inhibitory to the transport resistant cells. MTX(G5)-poly-L-Lys-52000 was approximately 1000 times more effective than MTX(G5)-poly-D-Lys-52000 in inhibiting the growth of H35R hepatoma cells in culture, indicating that internal cleavage of the gamma-glutamate chain of the conjugate with subsequent release of MTX or shorter chain polyglutamates of MTX is unlikely to be an important determinant of MTX-polyglutamate polylysine cytotoxicity. The results indicate that MTX-polyglutamate poly(L-lysine) conjugates are taken up by the cells independently of MTX and probably via endocytosis.