bis(pivaloyloxymethyl) N-{α-pivaloyloxymethyl-N-[4-(N-methyl)aminobenzoyl]-L-glutamyl-γ}-L-glutamate | 875668-02-3

• 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
• 英文名称: bis(pivaloyloxymethyl) N-{α-pivaloyloxymethyl-N-[4-(N-methyl)aminobenzoyl]-L-glutamyl-γ}-L-glutamate
• 英文别名: bis(2,2-dimethylpropanoyloxymethyl) (2S)-2-[[(4S)-5-(2,2-dimethylpropanoyloxymethoxy)-4-[[4-(methylamino)benzoyl]amino]-5-oxopentanoyl]amino]pentanedioate
• CAS: 875668-02-3
• 化学式: C₃₆H₅₃N₃O₁₄
• 分子量: 751.829
• InChiKey: XFOZSNVIRDEGJC-DQEYMECFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  53
• 可旋转键数：
  27
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.61
• 拓扑面积：
  228
• 氢给体数：
  3
• 氢受体数：
  15

反应信息

• 作为反应物：
  描述：

  bis(pivaloyloxymethyl) N-{α-pivaloyloxymethyl-N-[4-(N-methyl)aminobenzoyl]-L-glutamyl-γ}-L-glutamate 、 2,4-二氨基-6-羟甲基蝶啶盐酸盐 在 triphenylphosphine dibromide 1:1 addition complex 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基乙酰胺 为溶剂， 反应 50.0h， 以75%的产率得到bis(pivaloyloxymethyl) N-{N-[(4-deoxy-2,4-diamino-10-methyl)pteroyl]-α-pivaloyloxymethyl-L-glutamyl-γ}-L-glutamate
  参考文献：
  名称：

  Prodrug Forms of N-[(4-Deoxy-4-amino-10-methyl)pteroyl]glutamate-γ-[ψP(O)(OH)]-glutarate, a Potent Inhibitor of Folylpoly-γ-glutamate Synthetase: Synthesis and Hydrolytic Stability

  摘要：

  Ester prodrugs of the phosphinate pseudopeptide N-[(4-deoxy-4-amino-10-methyl)pteroyl]glutamate-gamma-[psi P(0)(OH)]-glutarate (1a) were synthesized. H-phosphinic acids derived from N-Cbz vinyl glycine esters were converted to the desired pseudopeptides by Michael addition to alpha-methyleneglutarate esters. Pivaloyloxymethyl (POM) ester moieties were incorporated in both the N-terminal and C-terminal fragments prior to formation of either C-P bond. N-Alkylation of the corresponding amides derived from p-(N-methyl)aminobenzoic acid with 2,4-diamino-6-(bromomethyl)pteridine gave the target compounds. POM esters of methotrexate and the corresponding gamma-glutamyl conjugate were also synthesized using the same strategy. All prodrugs were evaluated in Chinese hamster ovary cells. Although the pseudopeptide prodrugs were ineffective, prodrugs of methotrexate and the corresponding gamma-glutamyl conjugate were equipotent with the parent compounds. Stability of the prodrugs was investigated in both phosphate buffer and cell line medium to provide a rationale for the observed biological data.

  DOI：

  10.1021/jm050871p
• 作为产物：
  描述：

  N-(benzyloxycarbonyl)-4-(methylamino)benzoic acid 在 palladium on activated charcoal 1,1,2,3-四甲基胍 、 叠氮磷酸二苯酯 、 氢气 、 三乙胺 、 silver carbonate 、 三氟乙酸 、 甲基膦酸二甲酯 作用下， 以 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 57.0h， 生成 bis(pivaloyloxymethyl) N-{α-pivaloyloxymethyl-N-[4-(N-methyl)aminobenzoyl]-L-glutamyl-γ}-L-glutamate
  参考文献：
  名称：

  Prodrug Forms of N-[(4-Deoxy-4-amino-10-methyl)pteroyl]glutamate-γ-[ψP(O)(OH)]-glutarate, a Potent Inhibitor of Folylpoly-γ-glutamate Synthetase: Synthesis and Hydrolytic Stability

  摘要：

  Ester prodrugs of the phosphinate pseudopeptide N-[(4-deoxy-4-amino-10-methyl)pteroyl]glutamate-gamma-[psi P(0)(OH)]-glutarate (1a) were synthesized. H-phosphinic acids derived from N-Cbz vinyl glycine esters were converted to the desired pseudopeptides by Michael addition to alpha-methyleneglutarate esters. Pivaloyloxymethyl (POM) ester moieties were incorporated in both the N-terminal and C-terminal fragments prior to formation of either C-P bond. N-Alkylation of the corresponding amides derived from p-(N-methyl)aminobenzoic acid with 2,4-diamino-6-(bromomethyl)pteridine gave the target compounds. POM esters of methotrexate and the corresponding gamma-glutamyl conjugate were also synthesized using the same strategy. All prodrugs were evaluated in Chinese hamster ovary cells. Although the pseudopeptide prodrugs were ineffective, prodrugs of methotrexate and the corresponding gamma-glutamyl conjugate were equipotent with the parent compounds. Stability of the prodrugs was investigated in both phosphate buffer and cell line medium to provide a rationale for the observed biological data.

  DOI：

  10.1021/jm050871p