(S)-2-{4-[4-(4-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-butyrylamino)-butyrylamino]-butyrylamino}-pentanedioic acid di-tert-butyl ester | 103321-45-5

• 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: (S)-2-{4-[4-(4-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-butyrylamino)-butyrylamino]-butyrylamino}-pentanedioic acid di-tert-butyl ester
• CAS: 103321-45-5
• 化学式: C₄₀H₅₉N₁₁O₈
• 分子量: 821.977
• InChiKey: MOFDWJPYVSMHPT-NDEPHWFRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.47
• 重原子数：
  59.0
• 可旋转键数：
  21.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  275.84
• 氢给体数：
  6.0
• 氢受体数：
  15.0

反应信息

• 作为反应物：
  描述：

  (S)-2-{4-[4-(4-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-butyrylamino)-butyrylamino]-butyrylamino}-pentanedioic acid di-tert-butyl ester 在 三氟乙酸 作用下， 反应 0.17h， 以66%的产率得到(S)-2-{4-[4-(4-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-butyrylamino)-butyrylamino]-butyrylamino}-pentanedioic acid
  参考文献：
  名称：

  Methotrexate analogs. 29. Effect of .gamma.-aminobutyric acid spacers between the pteroyl and glutamate moieties on enzyme binding and cell growth inhibition

  摘要：

  A series of "stretched" methotrexate (MTX) analogues containing up to five 4-aminobutyryl (Gab) spacers between the 4-amino-4-deoxy-N10-methylpteroyl (MeAPA) moiety and the glutamate (Glu) side chain was prepared. Interest in these compounds stemmed from their relationship to MTX gamma-polyglutamates, from which they differ only in lacking "internal" alpha-carboxyl groups. The ability of the MeAPA-Gabn-Glu derivatives to inhibit dihydrofolate reductase (DHFR) and thymidylate synthase (TS) in vitro and to inhibit the growth of tumor cells in culture was evaluated. The IC50 for DHFR inhibition increased progressively from 0.082 to 0.84 microM as the number of Gab spacers was varied from one to five. At the same time the introduction of Gab spacers was found to produce substantial TS inhibition (Ki 0.1-0.4 microM) similar to that reported for MTX polyglutamates. Despite the activity of the MeAPA-Gabn-Glu derivatives as combined inhibitors of TS and DHFR, there was a steep loss of cell growth inhibitory potency as the number of Gab spacers was increased. This most likely reflects low cell uptake and the fact that when n greater than 1 there is almost total abolition of substrate activity for folylpolyglutamate synthetase, which had previously been observed with n = 1.

  DOI：

  10.1021/jm00160a014
• 作为产物：
  描述：

  L-谷氨酸二叔丁酯盐酸盐 在 palladium on activated charcoal 氰基磷酸二乙酯 、 二苯基膦叠氮化物 、 氢气 、 溶剂黄146 、 三乙胺 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 25.0 ℃ 、405.3 kPa 条件下， 生成 (S)-2-{4-[4-(4-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-butyrylamino)-butyrylamino]-butyrylamino}-pentanedioic acid di-tert-butyl ester
  参考文献：
  名称：

  Methotrexate analogs. 29. Effect of .gamma.-aminobutyric acid spacers between the pteroyl and glutamate moieties on enzyme binding and cell growth inhibition

  摘要：

  A series of "stretched" methotrexate (MTX) analogues containing up to five 4-aminobutyryl (Gab) spacers between the 4-amino-4-deoxy-N10-methylpteroyl (MeAPA) moiety and the glutamate (Glu) side chain was prepared. Interest in these compounds stemmed from their relationship to MTX gamma-polyglutamates, from which they differ only in lacking "internal" alpha-carboxyl groups. The ability of the MeAPA-Gabn-Glu derivatives to inhibit dihydrofolate reductase (DHFR) and thymidylate synthase (TS) in vitro and to inhibit the growth of tumor cells in culture was evaluated. The IC50 for DHFR inhibition increased progressively from 0.082 to 0.84 microM as the number of Gab spacers was varied from one to five. At the same time the introduction of Gab spacers was found to produce substantial TS inhibition (Ki 0.1-0.4 microM) similar to that reported for MTX polyglutamates. Despite the activity of the MeAPA-Gabn-Glu derivatives as combined inhibitors of TS and DHFR, there was a steep loss of cell growth inhibitory potency as the number of Gab spacers was increased. This most likely reflects low cell uptake and the fact that when n greater than 1 there is almost total abolition of substrate activity for folylpolyglutamate synthetase, which had previously been observed with n = 1.

  DOI：

  10.1021/jm00160a014