(1,1'-(4,8-bis(4-methoxybenzylamino)pyrimido[5,4-d]pyrimidine-2,6-diyl)bis(piperidine-3,1-diyl))dimethanol | 1415656-90-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: (1,1'-(4,8-bis(4-methoxybenzylamino)pyrimido[5,4-d]pyrimidine-2,6-diyl)bis(piperidine-3,1-diyl))dimethanol
• 英文别名: [1-[2-[3-(Hydroxymethyl)piperidin-1-yl]-4,8-bis[(4-methoxyphenyl)methylamino]pyrimido[5,4-d]pyrimidin-6-yl]piperidin-3-yl]methanol
• CAS: 1415656-90-4
• 化学式: C₃₄H₄₄N₈O₄
• 分子量: 628.775
• InChiKey: MTAATZBHNFULHU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  46
• 可旋转键数：
  12
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  141
• 氢给体数：
  4
• 氢受体数：
  12

反应信息

• 作为产物：
  描述：

  2,4,6,8-四氯嘧啶并[5,4-d]嘧啶 在 potassium carbonate 作用下， 以 四氢呋喃 为溶剂， 反应 1.0h， 生成 (1,1'-(4,8-bis(4-methoxybenzylamino)pyrimido[5,4-d]pyrimidine-2,6-diyl)bis(piperidine-3,1-diyl))dimethanol
  参考文献：
  名称：

  Novel pyrimidopyrimidine derivatives for inhibition of cellular proliferation and motility induced by h-prune in breast cancer

  摘要：

  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.

  DOI：

  10.1016/j.ejmech.2012.08.020

文献信息

• 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.