2-[[6-[Bis-(2-hydroxy-ethyl)-amino]-4,8-bis-(4-methoxy-benzylamino)-pyrimido[5,4-d]pyrimidin-2-yl]-(2-hydroxy-ethyl)-amino]-ethanol | 213839-95-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 2-[[6-[Bis-(2-hydroxy-ethyl)-amino]-4,8-bis-(4-methoxy-benzylamino)-pyrimido[5,4-d]pyrimidin-2-yl]-(2-hydroxy-ethyl)-amino]-ethanol
• 英文别名: 9NR6JP5Jpe；2-[[2-[bis(2-hydroxyethyl)amino]-4,8-bis[(4-methoxyphenyl)methylamino]pyrimido[5,4-d]pyrimidin-6-yl]-(2-hydroxyethyl)amino]ethanol
• CAS: 213839-95-3
• 化学式: C₃₀H₄₀N₈O₆
• 分子量: 608.698
• InChiKey: YLCHOQKGZQGCKW-UHFFFAOYSA-N

物化性质

• 熔点：
  204-205 °C(Solvent: Methanol ; Water)
• 沸点：
  888.5±75.0 °C(Predicted)
• 密度：
  1.393±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  44
• 可旋转键数：
  18
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  182
• 氢给体数：
  6
• 氢受体数：
  14

反应信息

• 作为产物：
  描述：

  2-[{6-[Bis-(2-hydroxy-ethyl)-amino]-4,8-bis-[(3,4-dimethoxy-benzyl)-(4-methoxy-benzyl)-amino]-pyrimido[5,4-d]pyrimidin-2-yl}-(2-hydroxy-ethyl)-amino]-ethanol 在 三氟乙酸 作用下， 生成 2-[[6-[Bis-(2-hydroxy-ethyl)-amino]-4,8-bis-(4-methoxy-benzylamino)-pyrimido[5,4-d]pyrimidin-2-yl]-(2-hydroxy-ethyl)-amino]-ethanol
  参考文献：
  名称：

  Resistance-modifying agents. Part 7: 2,6-disubstituted-4,8-dibenzylaminopyrimido[5,4- d ]pyrimidines that inhibit nucleoside transport in the presence of α 1 -acid glycoprotein (AGP)

  摘要：

  The synthesis and biological evaluation of potent 4,8-dibenzylaminopyrimidopyrimidine nucleoside transport inhibitors, with reduced binding to alpha(1)-acid glycoprotein, is reported. (C) 2000 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(00)00053-6

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.
• Novel pyrimidopyrimidine derivatives for inhibition of cellular proliferation and motility induced by h-prune in breast cancer
  作者：Antonella Virgilio、Daniela Spano、Veronica Esposito、Valeria Di Dato、Giuseppe Citarella、Natascia Marino、Veronica Maffia、Daniela De Martino、Pasqualino De Antonellis、Aldo Galeone、Massimo Zollo

  DOI：10.1016/j.ejmech.2012.08.020

  日期：2012.11

  The human (h)-prune protein is a member of the DHH protein superfamily and it has a cAMP phosphodiesterase activity. Its overexpression in breast, colorectal and gastric cancers correlates with depth of invasion and a high degree of lymph-node metastasis. One mechanism by which h-prune stimulates cell motility and metastasis processes is through its phosphodiesterase activity, which can be suppressed by dipyridamole, a pyrimido[5,4-d]pyrimidine analogue. To obtain new and more potent agents that have high specificity towards inhibition of this h-prune activity, we followed structure activity-relationship methodologies starting from dipyridamole and synthesised eight new pyrimido pyrimidine derivatives. We analysed these newly generated compounds for specificity towards h-prune activities in vitro in cellular models using scintillation proximity assay for cAMP-PDE activity, cell index in cell proliferation assays and transwell methodology for two-dimensional cell migration in a top-down strategy of selection. Our findings show that two pyrimido[5,4-d]pyrimidine compounds are more effective than dipyridamole in two highly metastatic cellular models of breast cancer in vitro. Future studies will assess their therapeutic effectiveness against breast and other cancers where there is over-expression of h-prune, and in ad-hoc, proof of concept, animal models. (C) 2012 Elsevier Masson SAS. All rights reserved.