4,8-bis[(3,4-dimethoxybenzyl)amino]-2,6-bis[(2-hydroxypropyl)amino]pyrimido[5,4-d]pyrimidine

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 4,8-bis[(3,4-dimethoxybenzyl)amino]-2,6-bis[(2-hydroxypropyl)amino]pyrimido[5,4-d]pyrimidine
• 英文别名: NU3108；1-[[4,8-Bis[(3,4-dimethoxyphenyl)methylamino]-2-(2-hydroxypropylamino)pyrimido[5,4-d]pyrimidin-6-yl]amino]propan-2-ol
• 化学式: C₃₀H₄₀N₈O₆
• 分子量: 608.698
• InChiKey: TZNGEPFGWXQHNH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  44
• 可旋转键数：
  16
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  177
• 氢给体数：
  6
• 氢受体数：
  14

反应信息

• 作为反应物：
  描述：

  4,8-bis[(3,4-dimethoxybenzyl)amino]-2,6-bis[(2-hydroxypropyl)amino]pyrimido[5,4-d]pyrimidine 在 吡啶 、 4-二甲氨基吡啶 作用下， 以 四氢呋喃 为溶剂， 反应 53.0h， 生成 4-((1-((4,8-bis((3,4-dimethoxybenzyl)amino)-6-((2-((phenylcarbamoyl)oxy)propyl)-amino)pyrimido[5,4-d]pyrimidin-2-yl)amino)propan-2-yl)oxy)-4-oxobutanoic acid
  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
• 作为产物：
  描述：

  3,4-二甲氧基苄胺 在 potassium carbonate 作用下， 以 四氢呋喃 为溶剂， 生成 4,8-bis[(3,4-dimethoxybenzyl)amino]-2,6-bis[(2-hydroxypropyl)amino]pyrimido[5,4-d]pyrimidine
  参考文献：
  名称：

  Resistance-Modifying Agents. 11. Pyrimido[5,4-d]pyrimidine Modulators of Antitumor Drug Activity. Synthesis and Structure−Activity Relationships for Nucleoside Transport Inhibition and Binding to α₁-Acid Glycoprotein

  摘要：

  The cardiovascular and antithrombotic agent dipyridamole (DP) has potential therapeutic utility as a modulator of the activity of antimetabolite antitumor agents by virtue of its inhibition of nucleoside transport. However, the activity of DP can be compromised by binding to the acute phase serum protein, alpha(1)-acid glycoprotein (AGP). Analogues of DP were synthesized and evaluated as inhibitors of H-3-thymidine uptake into L1210 leukamia cells in the presence and absence of 5 mg/mL AGP. Compounds with potency similar to that of DP were identified where the piperidino substituents at the 4,8-positions were replaced by 4'-methoxybenzylamino, 3',4'dimethoxybenzylamino, or piperonylamino groups. Replacement of the diethanolamino groups at the 2,6-positions of DP by alkylamino or alkoxy substituents was tolerated, although at least one oxygen-bearing function (hydroxyl or alkoxy) was required in the side chain for activity comparable to that of DP. Whereas AGP completely ablated the activity of DP, the majority of the newer compounds synthesized retained significant activity in the presence of excess AGP, although replacement of the piperidino groups at the 4,8-positions by N-methylbenzylamino substituents did, in some cases, restore susceptibility to AGP. Selected compounds have been demonstrated to prevent rescue from antifolate cytotoxicity, mediated by nucleoside salvage.

  DOI：

  10.1021/jm040772w

文献信息

• Resistance-Modifying Agents. 11. Pyrimido[5,4-<i>d</i>]pyrimidine Modulators of Antitumor Drug Activity. Synthesis and Structure−Activity Relationships for Nucleoside Transport Inhibition and Binding to α₁-Acid Glycoprotein
  作者：Nicola J. Curtin、Hannah C. Barlow、Karen J. Bowman、A. Hilary Calvert、Richard Davison、Bernard T. Golding、Bing Huang、Peter J. Loughlin、David R. Newell、Peter G. Smith、Roger J. Griffin

  DOI：10.1021/jm040772w

  日期：2004.9.1

  The cardiovascular and antithrombotic agent dipyridamole (DP) has potential therapeutic utility as a modulator of the activity of antimetabolite antitumor agents by virtue of its inhibition of nucleoside transport. However, the activity of DP can be compromised by binding to the acute phase serum protein, alpha(1)-acid glycoprotein (AGP). Analogues of DP were synthesized and evaluated as inhibitors of H-3-thymidine uptake into L1210 leukamia cells in the presence and absence of 5 mg/mL AGP. Compounds with potency similar to that of DP were identified where the piperidino substituents at the 4,8-positions were replaced by 4'-methoxybenzylamino, 3',4'dimethoxybenzylamino, or piperonylamino groups. Replacement of the diethanolamino groups at the 2,6-positions of DP by alkylamino or alkoxy substituents was tolerated, although at least one oxygen-bearing function (hydroxyl or alkoxy) was required in the side chain for activity comparable to that of DP. Whereas AGP completely ablated the activity of DP, the majority of the newer compounds synthesized retained significant activity in the presence of excess AGP, although replacement of the piperidino groups at the 4,8-positions by N-methylbenzylamino substituents did, in some cases, restore susceptibility to AGP. Selected compounds have been demonstrated to prevent rescue from antifolate cytotoxicity, mediated by nucleoside salvage.
• Nucleoside Transport Inhibitors: Structure−Activity Relationships for Pyrimido[5,4-<i>d</i>]pyrimidine Derivatives That Potentiate Pemetrexed Cytotoxicity in the Presence of α₁-Acid Glycoprotein
  作者：Kappusamy Saravanan、Hannah C. Barlow、Marion Barton、A. Hilary Calvert、Bernard T. Golding、David R. Newell、Julian S. Northen、Nicola J. Curtin、Huw D. Thomas、Roger J. Griffin

  DOI：10.1021/jm101493z

  日期：2011.3.24

  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.