methyl (2S)-2-{N-[α-methyl-N-(benzyloxycarbonyl)-L-γ-glutamyl]amino}-4-(1-methoxycarbonylmethyltetrazol-5-yl)butyrate | 174488-04-1

• 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: methyl (2S)-2-{N-[α-methyl-N-(benzyloxycarbonyl)-L-γ-glutamyl]amino}-4-(1-methoxycarbonylmethyltetrazol-5-yl)butyrate
• 英文别名: methyl (2S)-5-[[(2S)-1-methoxy-4-[1-(2-methoxy-2-oxoethyl)tetrazol-5-yl]-1-oxobutan-2-yl]amino]-5-oxo-2-(phenylmethoxycarbonylamino)pentanoate
• CAS: 174488-04-1
• 化学式: C₂₃H₃₀N₆O₉
• 分子量: 534.526
• InChiKey: QNSVKQTWUINZCO-IRXDYDNUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  38
• 可旋转键数：
  18
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  190
• 氢给体数：
  2
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  methyl (2S)-2-{N-[α-methyl-N-(benzyloxycarbonyl)-L-γ-glutamyl]amino}-4-(1-methoxycarbonylmethyltetrazol-5-yl)butyrate 在 10percent Pd/C 氢气 、 三乙胺 、 焦碳酸二乙酯 作用下， 以 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 23.0h， 生成 methyl (2S)-2-{N-{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}-α-methyl-L-γ-glutamyl}amino}-4-(1-methoxycarbonylmethyltetrazol-5-yl)butyrate
  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-L-GluOMe 在 N-甲基吗啉 作用下， 以 四氢呋喃 为溶剂， 反应 1.84h， 生成 methyl (2S)-2-{N-[α-methyl-N-(benzyloxycarbonyl)-L-γ-glutamyl]amino}-4-(1-methoxycarbonylmethyltetrazol-5-yl)butyrate
  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

• Design and Synthesis of Cyclopenta[<i>g</i>]quinazoline-Based Antifolates as Inhibitors of Thymidylate Synthase and Potential Antitumor Agents^,
  作者：Vassilios Bavetsias、Jonathan H. Marriott、Camille Melin、Rosemary Kimbell、Zbigniew S. Matusiak、F. Thomas Boyle、Ann L. Jackman

  DOI：10.1021/jm991119p

  日期：2000.5.1

  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.