2,6-dichloro-4,8-bis-(dibenzylamino)pyrimido[5,4-d]pyrimidine | 774539-00-3

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 2,6-dichloro-4,8-bis-(dibenzylamino)pyrimido[5,4-d]pyrimidine
• 英文别名: 4-N,4-N,8-N,8-N-tetrabenzyl-2,6-dichloropyrimido[5,4-d]pyrimidine-4,8-diamine
• CAS: 774539-00-3
• 化学式: C₃₄H₂₈Cl₂N₆
• 分子量: 591.543
• InChiKey: UYPYKSMTZUBRLR-UHFFFAOYSA-N

物化性质

• 熔点：
  141-143 °C(Solv: ethyl acetate (141-78-6); ligroine (8032-32-4))
• 沸点：
  710.9±60.0 °C(Predicted)
• 密度：
  1.347±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  8.7
• 重原子数：
  42
• 可旋转键数：
  10
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  58
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2,6-dichloro-4,8-bis-(dibenzylamino)pyrimido[5,4-d]pyrimidine 在 palladium on activated charcoal 甲醇 、 氢气 、 sodium hydride 、 乙酰氯 作用下， 以 四氢呋喃 为溶剂， 反应 5.08h， 生成 4-N,8-N-dibenzyl-2,6-bis(2-methoxyethoxy)pyrimido[5,4-d]pyrimidine-4,8-diamine
  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
• 作为产物：
  描述：

  1,5-dihydropyrimido[5,4-d]pyrimidine-2,4,6,8-(3H,7H)-tetrone 在 sodium hydroxide 、 potassium carbonate 作用下， 以 四氢呋喃 为溶剂， 反应 8.33h， 生成 2,6-dichloro-4,8-bis-(dibenzylamino)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

• Synthesis, Flow Cytometric Evaluation, and Identification of Highly Potent Dipyridamole Analogues as Equilibrative Nucleoside Transporter 1 Inhibitors
  作者：Wenwei Lin、John K. Buolamwini

  DOI：10.1021/jm070311l

  日期：2007.8.1

  Dipyridamole (Persantine) is a clinically used vasodilator with equilibrative nucleoside transporters I and 2 (ENT1 and ENT2) inhibitory activity albeit less potent than the prototype ENT1 inhibitor nitrobenzylmercaptopurine riboside (NBMPR). Dipyridamole is a good candidate for further exploration because it is a non-nucleoside and has a proven record of safe use in humans. A series of dipyridamole analogues were synthesized with systematic modification and evaluated as ENT1 inhibitors by flow cytometry. Compounds with much higher potency were identified, the best being 2,6-bis(diethanolamino)-4,8-diheptamethylene-iminopyrimido[5,4-d]pyrimidine (13) with a K-i of 0.49 nM compared to a Ki of 308 nM for dipyridamole. Compound 13 is similar in potency to the prototype potent ENT1 inhibitor NBMPR (0.43 nM). For the first time, a dipyridamole analogue has been identified that is equipotent with NBMPR. The SAR indicated that diethanolamine substituted analogues were more active than monoethanolamine compounds. Also, free hydroxyl groups are not essential for activity.