(1R)-N-[N-(benzyloxycarbonyl)-α-tert-butyl-L-γ-glutamyl]-1-(5-tetrazolyl)ethylamine | 277758-48-2

• 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: (1R)-N-[N-(benzyloxycarbonyl)-α-tert-butyl-L-γ-glutamyl]-1-(5-tetrazolyl)ethylamine
• 英文别名: tert-butyl (2S)-5-oxo-2-(phenylmethoxycarbonylamino)-5-[[(1R)-1-(2H-tetrazol-5-yl)ethyl]amino]pentanoate
• CAS: 277758-48-2
• 化学式: C₂₀H₂₈N₆O₅
• 分子量: 432.48
• InChiKey: AJDCTYNZHQAPDH-HIFRSBDPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  31
• 可旋转键数：
  12
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  148
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (1R)-N-[N-(benzyloxycarbonyl)-α-tert-butyl-L-γ-glutamyl]-1-(5-tetrazolyl)ethylamine 在 10percent Pd/C 氢气 、 1-羟基苯并三唑 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 生成 (1R)-N-{α-tert-butyl-N-{4-[N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzoyl}-L-γ-glutamyl}-1-(5-tetrazolyl)ethylamine
  参考文献：
  名称：

  Design and Synthesis of Cyclopenta[g]quinazoline-Based Antifolates as Inhibitors of Thymidylate Synthase and Potential Antitumor Agents^,

  摘要：

  Following the development of raltitrexed, the synthesis of nonpolyglutamatable inhibitors of TS that do not use the reduced folate carrier (RFC) for cellular entry should provide compounds which overcome mechanisms of resistance to folate-based inhibitors of TS that are associated with decreased/altered folylpolyglutamate synthetase (FPGS) expression and/or an impaired RFC. Examination of a computer graphics model of the humanized Escherichia coli TS enzyme with quinazoline inhibitors of TS, such as 1 bound in the active site of the enzyme, suggested that conformational restriction introduced by bridging the C9 with C7 to form a pentacycle may be beneficial for binding to TS. That led to the synthesis of a series of potent cyclopenta[g]quinazoline-based inhibitors of the enzyme in which the glutamyl residue associated with classical antifolates was replaced with a variety of glutamate-derived ligands; the most potent inhibitor being the L-Glu-gamma-D-GluT(alpha) derivative 7j. In the mouse L1210:1565 cell line (mutant RFC), the majority of these compounds had activity equal or only slightly greater compared with the parental L1210 cell line, indicating a reduced dependence on the RFC for cellular uptake in the L1210 cell line.

  DOI：

  10.1021/jm991119p
• 作为产物：
  描述：

  Z-谷安酸叔丁基酯 在 N-甲基吗啉 作用下， 以 四氢呋喃 为溶剂， 反应 4.34h， 生成 (1R)-N-[N-(benzyloxycarbonyl)-α-tert-butyl-L-γ-glutamyl]-1-(5-tetrazolyl)ethylamine
  参考文献：
  名称：

  Design and Synthesis of Cyclopenta[g]quinazoline-Based Antifolates as Inhibitors of Thymidylate Synthase and Potential Antitumor Agents^,

  摘要：

  Following the development of raltitrexed, the synthesis of nonpolyglutamatable inhibitors of TS that do not use the reduced folate carrier (RFC) for cellular entry should provide compounds which overcome mechanisms of resistance to folate-based inhibitors of TS that are associated with decreased/altered folylpolyglutamate synthetase (FPGS) expression and/or an impaired RFC. Examination of a computer graphics model of the humanized Escherichia coli TS enzyme with quinazoline inhibitors of TS, such as 1 bound in the active site of the enzyme, suggested that conformational restriction introduced by bridging the C9 with C7 to form a pentacycle may be beneficial for binding to TS. That led to the synthesis of a series of potent cyclopenta[g]quinazoline-based inhibitors of the enzyme in which the glutamyl residue associated with classical antifolates was replaced with a variety of glutamate-derived ligands; the most potent inhibitor being the L-Glu-gamma-D-GluT(alpha) derivative 7j. In the mouse L1210:1565 cell line (mutant RFC), the majority of these compounds had activity equal or only slightly greater compared with the parental L1210 cell line, indicating a reduced dependence on the RFC for cellular uptake in the L1210 cell line.

  DOI：

  10.1021/jm991119p

文献信息

• Carboxylic acid bioisosteres of γ-linked dipeptide analogues of the folate-based thymidylate synthase (TS) inhibitor, 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583)
  作者：Vassilios Bavetsias、Ann L. Jackman、Rosemary Kimbell、F. Thomas Boyle、Graham M.F. Bisset

  DOI：10.1016/0960-894x(96)00078-9

  日期：1996.3

  Tetrazole carboxylic acid bioisosteres of gamma-linked dipeptide derivatives of 2-desamino-2-methyl-N-10-propargyl-5,8-dideazafolic acid (ICI 198583), a folate-based inhibitor of thymidylate synthase (TS), were synthesised by multistep routes starting from the appropriate pteroic acid analogue and Z-D-Ala or D-Glu. They exhibited excellent TS inhibitory activities which, however, were not accompanied by a parallel improvement in the L1210 cell growth inhibition.