2,2',2'',2'''-tetrakis-acetoxy-1,1',1'',1'''-(4,8-di-piperidin-1-yl-pyrimido[5,4-d]pyrimidin-2,6-diylbisazanediyl)-tetrakis-ethane | 63023-20-1

• 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: 2,2',2'',2'''-tetrakis-acetoxy-1,1',1'',1'''-(4,8-di-piperidin-1-yl-pyrimido[5,4-d]pyrimidin-2,6-diylbisazanediyl)-tetrakis-ethane
• 英文别名: 2-[(6-{Bis[2-(acetyloxy)ethyl]amino}-4,8-bis(piperidin-1-yl)pyrimido[5,4-d][1,3]diazin-2-yl)[2-(acetyloxy)ethyl]amino]ethyl acetate；2-[2-acetyloxyethyl-[2-[bis(2-acetyloxyethyl)amino]-4,8-di(piperidin-1-yl)pyrimido[5,4-d]pyrimidin-6-yl]amino]ethyl acetate
• CAS: 63023-20-1
• 化学式: C₃₂H₄₈N₈O₈
• 分子量: 672.782
• InChiKey: NAQKJRWKMHLFAE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  48
• 可旋转键数：
  20
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.69
• 拓扑面积：
  170
• 氢给体数：
  0
• 氢受体数：
  16

反应信息

• 作为产物：
  描述：

  乙酰氯 、 双嘧达莫 在 4-二甲氨基吡啶 作用下， 以 四氢呋喃 为溶剂， 反应 3.0h， 以95%的产率得到2,2',2'',2'''-tetrakis-acetoxy-1,1',1'',1'''-(4,8-di-piperidin-1-yl-pyrimido[5,4-d]pyrimidin-2,6-diylbisazanediyl)-tetrakis-ethane
  参考文献：
  名称：

  Synthesis, Flow Cytometric Evaluation, and Identification of Highly Potent Dipyridamole Analogues as Equilibrative Nucleoside Transporter 1 Inhibitors

  摘要：

  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.

  DOI：

  10.1021/jm070311l

文献信息

• Synthesis, characterization and interaction with ionic micelles of tetraacetylated dipyridamole
  作者：Christiane P.F Borges、Shinya Honda、Roberto G.S Berlinck、Hidetake Imasato、Pedro Berci Filho、Marcel Tabak

  DOI：10.1016/0584-8539(95)01432-2

  日期：1995.12

  Tetraacetylated dipyridamole (Ac-DIP) was synthesized by reaction of dipynidamole (DIP) with acetic anhydride in a quantitative yield. Infrared and NMR spectra showed that the acetylation was complete, yielding the expected new bands and the disappearance of hydroxyl bands in the IR and NMR spectra. Tetraacetylated DIP was analyzed by electronic absorption and fluorescence emission in different solvents. The solubility of Ac-DIP in water is considerably lower than that of DIP, and both the absorption and emission are shifted to the blue denoting a less efficient relaxation to the solvent. Extinction coefficients and quantum yields in ethanol, chloroform and dimethyl sulfoxide are very similar for Ac-DIP and DIP. H-1 and C-13 NMR spectra were obtained in deuterated chloroform and dimethyl sulfoxide and a complete assignment of peaks was obtained. In order to obtain more insight into the properties of Ac-DIP, the interaction of DIP and Ac-DIP with cationic cetyltrimethylammonium chloride (CTAC) and anionic sodium dodecyl sulfate (SDS) micelles was studied. In the presence of micelles the pK(a) of DIP changes considerably from its value in water: from 5.8 to 4.3 in CTAC and to 7.3 in SDS indicating a considerable interaction with micelles. The pK(a) of Ac-DIP in SDS is 5.8. For both compounds the interaction with micelles is predominantly hydrophobic in nature but for Ac-DIP it is less sensitive to the charge on the micelle and the degree of ionization of the drug. All the results suggest that Ac-DIP is significantly more hydrophobic than DIP, being probably quite efficient in the interaction with membrane systems. This could be quite relevant for its effect at the cellular level.
• 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.