tert-butyl (4R)-4-[N-(α-tert-butyl-L-γ-glutamyl)amino]-4-(5-tetrazolyl)butyrate | 174488-23-4

• 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: tert-butyl (4R)-4-[N-(α-tert-butyl-L-γ-glutamyl)amino]-4-(5-tetrazolyl)butyrate
• 英文别名: tert-butyl (2S)-2-amino-5-[[(1R)-4-[(2-methylpropan-2-yl)oxy]-4-oxo-1-(2H-tetrazol-5-yl)butyl]amino]-5-oxopentanoate
• CAS: 174488-23-4
• 化学式: C₁₈H₃₂N₆O₅
• 分子量: 412.489
• InChiKey: YREYVRBSXCHRKM-NWDGAFQWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.1
• 重原子数：
  29
• 可旋转键数：
  13
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.78
• 拓扑面积：
  162
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  tert-butyl (4R)-4-[N-(α-tert-butyl-L-γ-glutamyl)amino]-4-(5-tetrazolyl)butyrate 在 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 7.0h， 生成 (S)-4-[(R)-3-Carboxy-1-(1H-tetrazol-5-yl)-propylcarbamoyl]-2-{4-[(2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)-prop-2-ynyl-amino]-benzoylamino}-butyric acid
  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-D-叔丁基谷氨酸 在 10percent Pd/C 吡啶 、 sodium azide 、 氨 、 氢气 、 氯化铵 、 三乙胺 、 三氯氧磷 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 78.42h， 生成 tert-butyl (4R)-4-[N-(α-tert-butyl-L-γ-glutamyl)amino]-4-(5-tetrazolyl)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

• Cyclopenta[g]quinazoline-based antifolates: the effect of the chirality at the 6-position on the inhibition of thymidylate synthase (TS)
  作者：V. Bavetsias、J.H. Marriott、D.S. Theti、J.C. Melin、S.C. Wilson、A.L. Jackman

  DOI：10.1016/s0960-894x(01)00612-6

  日期：2001.12

  inhibitors of thymidylate synthase (TS) possess a chiral centre at the 6-position of the molecule. The effect of this chirality on the inhibition of TS was investigated by synthesising compounds 6S-1a-c, 6R-1a-c. It was shown, in particular with the diastereoisomers 6S-1c, 6R-1c, that the inhibitory activity against TS is mainly due to the 6S diastereoisomer rather than the 6R diastereoisomer, which is

  胸苷酸合酶（TS）的基于环戊[g]喹唑啉的抑制剂在分子的6-位具有手性中心。通过合成化合物6S-1a-c，6R-1a-c，研究了这种手性对TS抑制的影响。已显示，特别是对于非对映异构体6S-1c，6R-1c，对TS的抑制活性主要归因于6S非对映异构体，而不是实际上无活性的6R非对映异构体。
• 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.