(2S)-methyl 2-((((1-((4,8-bis((3,4-dimethoxybenzyl)amino)-6-((2-hydroxypropyl)amino)-pyrimido[5,4-d]pyrimidin-2-yl)amino)propan-2-yl)oxy)carbonyl)amino)-3-methylbutanoate | 1280167-63-6

• 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: (2S)-methyl 2-((((1-((4,8-bis((3,4-dimethoxybenzyl)amino)-6-((2-hydroxypropyl)amino)-pyrimido[5,4-d]pyrimidin-2-yl)amino)propan-2-yl)oxy)carbonyl)amino)-3-methylbutanoate
• 英文别名: methyl (2S)-2-[1-[[4,8-bis[(3,4-dimethoxyphenyl)methylamino]-6-(2-hydroxypropylamino)pyrimido[5,4-d]pyrimidin-2-yl]amino]propan-2-yloxycarbonylamino]-3-methylbutanoate
• CAS: 1280167-63-6
• 化学式: C₃₇H₅₁N₉O₉
• 分子量: 765.867
• InChiKey: ZQWXVKQOMHCSIC-NRVWMRPUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  55
• 可旋转键数：
  22
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  222
• 氢给体数：
  6
• 氢受体数：
  17

反应信息

• 作为产物：
  描述：

  (S)-(-)-2-异氰酰基-3-甲基丁酸 、 4,8-bis[(3,4-dimethoxybenzyl)amino]-2,6-bis[(2-hydroxypropyl)amino]pyrimido[5,4-d]pyrimidine 以 四氢呋喃 为溶剂， 反应 48.0h， 以16%的产率得到(2S)-methyl 2-((((1-((4,8-bis((3,4-dimethoxybenzyl)amino)-6-((2-hydroxypropyl)amino)-pyrimido[5,4-d]pyrimidin-2-yl)amino)propan-2-yl)oxy)carbonyl)amino)-3-methylbutanoate
  参考文献：
  名称：

  Nucleoside Transport Inhibitors: Structure−Activity Relationships for Pyrimido[5,4-d]pyrimidine Derivatives That Potentiate Pemetrexed Cytotoxicity in the Presence of α₁-Acid Glycoprotein

  摘要：

  Membrane transport of nucleosides or nucleobases is mediated by transporters including the equilibrative nucleoside transporters (ENTs), and resistance to antitumor antimetabolite drugs may arise via salvage of exogenous purine or pyrimidine nucleosides or nucleobases by ENT transporters. The therapeutic utility of dipyridamole (3), a potent ENT inhibitor, is compromised by binding to the serum protein alpha(1)-acid glycoprotein (AGP). Derivatives and prodrugs of the ENT inhibitor 4,8-bis[(3,4-dimethoxybenzyl)amino]-2,6-bis[(2-hydroxypropyl)amino]pyrimido[5,4-d]pyrimidine (6, NU3108) are described, with improved in vivo pharmacokinetic properties and reduced AGP binding relative to dipyridamole. The mono- and diglycine carbamate derivatives were at least as potent as 6 and showed no reduction in potency by AGP. In a [H-3]thymidine incorporation assay, employing COR-L23 cells, the diastereoisomers of 6 (IC50 = 26 nM) exhibited activity comparable with 3 (IC50 = 15 nM). The monophenyl carbamate and mono-4-methoxyphenyl carbamate exhibited the best ENT-inhibitory activity in the COR-L23 assay (IC50 =8 and 4 nM, respectively). All of the new prodrugs were also highly effective at reversing thymidine/hypoxanthine rescue from pemetrexed cytotoxicity in the COR-L23 cell line.

  DOI：

  10.1021/jm101493z