diethyl N-{4-[4-(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)butyl]benzoyl}-L-glutamate | 863767-94-6

• 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: diethyl N-{4-[4-(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)butyl]benzoyl}-L-glutamate
• 英文别名: diethyl (2S)-2-[[4-[4-(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)butyl]benzoyl]amino]pentanedioate
• CAS: 863767-94-6
• 化学式: C₂₆H₃₃N₅O₆
• 分子量: 511.578
• InChiKey: LVRYZYLQOHLZJS-IBGZPJMESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  37
• 可旋转键数：
  15
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  173
• 氢给体数：
  3
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  diethyl N-{4-[4-(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)butyl]benzoyl}-L-glutamate 在 sodium hydroxide 作用下， 以 甲醇 为溶剂， 反应 16.0h， 以92%的产率得到(S)-2-{4-[4-(2,4-Diamino-furo[2,3-d]pyrimidin-5-yl)-butyl]-benzoylamino}-pentanedioic acid
  参考文献：
  名称：

  Synthesis of Classical, Four-Carbon Bridged 5-Substituted Furo[2,3-d]pyrimidine and 6-Substituted Pyrrolo[2,3-d]pyrimidine Analogues as Antifolates

  摘要：

  We report, for the first time, the biological activities of four-carbon-atom bridged classical antifolates on dihydrofolate reductase (DHFR), thymidylate synthase (TS), and folylpolyglutamate synthetase (FPGS) as well as antitumor activity. Extension of the bridge homologation studies of classical two-carbon bridged antifolates, a 5-substituted 2,4-diaminofuro[2,3d]pyrimidine (1) and a 6-subsituted 2-amino-4-oxopyrrolo[2,3-d]pyrimidine (2), afforded two four-carbon bridged antifolates, analogues 5 and 6, with enhanced FPGS substrate activity and inhibitory activity against tumor cells in culture (EC50 <= 10(-7) M) compared with the two-carbon bridged analogues. These results support our original hypothesis that the distance and orientation of the side chain p-aminobenzoyl-L-glutamate moiety with respect to the pyrimidine ring are a crucial determinant of biological activity. In addition, this study demonstrates that, for classical antifolates that are substrates for FPGS, poor inhibitory activity against isolated target enzymes is not necessarily a predictor of a lack of antitumor activity.

  DOI：

  10.1021/jm058213s
• 作为产物：
  描述：

  (3-丙羧基)三苯基溴化膦 在 palladium on activated charcoal sodium hydroxide 、 草酰氯 、 氢气 、 sodium hydride 、 三乙胺 、 氯甲酸异丁酯 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 二氯甲烷 、 氯仿 、 二甲基亚砜 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 50.0 ℃ 、344.74 kPa 条件下， 反应 128.5h， 生成 diethyl N-{4-[4-(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)butyl]benzoyl}-L-glutamate
  参考文献：
  名称：

  Synthesis of Classical, Four-Carbon Bridged 5-Substituted Furo[2,3-d]pyrimidine and 6-Substituted Pyrrolo[2,3-d]pyrimidine Analogues as Antifolates

  摘要：

  We report, for the first time, the biological activities of four-carbon-atom bridged classical antifolates on dihydrofolate reductase (DHFR), thymidylate synthase (TS), and folylpolyglutamate synthetase (FPGS) as well as antitumor activity. Extension of the bridge homologation studies of classical two-carbon bridged antifolates, a 5-substituted 2,4-diaminofuro[2,3d]pyrimidine (1) and a 6-subsituted 2-amino-4-oxopyrrolo[2,3-d]pyrimidine (2), afforded two four-carbon bridged antifolates, analogues 5 and 6, with enhanced FPGS substrate activity and inhibitory activity against tumor cells in culture (EC50 <= 10(-7) M) compared with the two-carbon bridged analogues. These results support our original hypothesis that the distance and orientation of the side chain p-aminobenzoyl-L-glutamate moiety with respect to the pyrimidine ring are a crucial determinant of biological activity. In addition, this study demonstrates that, for classical antifolates that are substrates for FPGS, poor inhibitory activity against isolated target enzymes is not necessarily a predictor of a lack of antitumor activity.

  DOI：

  10.1021/jm058213s

文献信息

• Synthesis of Classical, Four-Carbon Bridged 5-Substituted Furo[2,3-<i>d</i>]pyrimidine and 6-Substituted Pyrrolo[2,3-<i>d</i>]pyrimidine Analogues as Antifolates
  作者：Aleem Gangjee、Yibin Zeng、John J. McGuire、Roy L. Kisliuk

  DOI：10.1021/jm058213s

  日期：2005.8.1

  We report, for the first time, the biological activities of four-carbon-atom bridged classical antifolates on dihydrofolate reductase (DHFR), thymidylate synthase (TS), and folylpolyglutamate synthetase (FPGS) as well as antitumor activity. Extension of the bridge homologation studies of classical two-carbon bridged antifolates, a 5-substituted 2,4-diaminofuro[2,3d]pyrimidine (1) and a 6-subsituted 2-amino-4-oxopyrrolo[2,3-d]pyrimidine (2), afforded two four-carbon bridged antifolates, analogues 5 and 6, with enhanced FPGS substrate activity and inhibitory activity against tumor cells in culture (EC50 <= 10(-7) M) compared with the two-carbon bridged analogues. These results support our original hypothesis that the distance and orientation of the side chain p-aminobenzoyl-L-glutamate moiety with respect to the pyrimidine ring are a crucial determinant of biological activity. In addition, this study demonstrates that, for classical antifolates that are substrates for FPGS, poor inhibitory activity against isolated target enzymes is not necessarily a predictor of a lack of antitumor activity.