dibenzyl ((dodecane-1,12-diylbis(azanediyl))bis(6-oxohexane-6,1-diyl))dicarbamate | 104807-21-8

• 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: dibenzyl ((dodecane-1,12-diylbis(azanediyl))bis(6-oxohexane-6,1-diyl))dicarbamate
• 英文别名: benzyl N-[6-oxo-6-[12-[6-(phenylmethoxycarbonylamino)hexanoylamino]dodecylamino]hexyl]carbamate
• CAS: 104807-21-8
• 化学式: C₄₀H₆₂N₄O₆
• 分子量: 694.955
• InChiKey: IGMIYRYBRDBEBS-UHFFFAOYSA-N

物化性质

• 沸点：
  887.2±65.0 °C(Predicted)
• 密度：
  1.071±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  8
• 重原子数：
  50
• 可旋转键数：
  31
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  135
• 氢给体数：
  4
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  dibenzyl ((dodecane-1,12-diylbis(azanediyl))bis(6-oxohexane-6,1-diyl))dicarbamate 在 palladium on activated charcoal dimethyl sulfide borane 、 氢气 作用下， 生成 N~1~,N~12~-Bis(6-aminohexyl)dodecane-1,12-diamine
  参考文献：
  名称：

  Differential blockade of muscarinic receptor subtypes by polymethylene tetraamines. Novel class of selective antagonists of cardiac M-2 muscarinic receptors

  摘要：

  Several N,N'-bis[6-[(2-methoxybenzyl)amino]hexyl]-1, omega-alkanediamine tetrahydrochlorides were synthesized and evaluated for their blocking activity on muscarinic receptors in guinea pig atria and rat ileum and bladder. The results were compared with those obtained for the classical nonselective muscarinic antagonist atropine. It was discovered that optimum activity is associated with an eight-carbon chain (compound 4) in guinea pig atria whereas, in both rat ileum and bladder, the 12-carbon analogue 7 had the highest activity. In addition, polymethylene tetraamines 1-6 displayed high selectivity toward guinea pig atria muscarinic receptors. The discriminatory power of 1-6 was not shared by 7. All the tetraamines were shown to be competitive antagonists of muscarinic receptors. N,N'-Bis[6-[(2-methoxybenzyl)amino]hexyl]-1,8-octanediamine was the most potent and selective toward muscarinic receptors in atria, with a pA2 value of 8.13 and a selectivity ratio (atria vs. ileum or bladder) of ca. 270. At a concentration of 10 microM, tetraamine 4 did not affect histamine and 5-hydroxytryptamine receptors of guinea pig ileum or alpha-adrenoreceptors of guinea pig atria whereas it inhibited postsynaptic alpha-adrenoreceptors of rat vas deferens with a -log K value of 5.23 and nicotinic receptors of frog rectus abdominis with an IC50 value of 0.23 microM. It is concluded that 4 is a novel, powerful, and selective tool in the characterization of muscarinic receptor subtypes.

  DOI：

  10.1021/jm00384a034
• 作为产物：
  描述：

  1,12-二氨基十二烷 、 氯甲酸乙酯 在 N-苄氧羰基--6-氨基己酸 、 三乙胺 作用下， 以 1,4-二氧六环 为溶剂， 反应 18.5h， 以84%的产率得到dibenzyl ((dodecane-1,12-diylbis(azanediyl))bis(6-oxohexane-6,1-diyl))dicarbamate
  参考文献：
  名称：

  Synthetic polyamines activating autophagy: Effects on cancer cell death

  摘要：

  The ability of symmetrically substituted long chain polymethylene tetramines, methoctramine (1) and its analogs 2-4 to kill cancer cells was studied. We found that an elevated cytotoxicity was correlated with a 12 methylene chain length separating the inner amine functions (6-12-6 carbon backbone), together with the introduction of diphenylethyl moieties on the terminal nitrogen atoms (compound 4) of a tetramine backbone. Compound 4 triggered dissipation of mitochondrial transmembrane potential and increased intracellular peroxide levels, leading to a caspase-independent HeLa cell death associated with a rapid activation of autophagy. The antioxidant N-acetylcysteine inhibited cell death and activation of autophagy, indicating a link between oxidative stress and autophagy. Autophagy was rapidly triggered even by tetramines 2 and 3, indicating that is related to their polyamine structure. Autophagy did not protect HeLa cells against cytotoxicity elicited by compound 4. The present study shows that, by modifications of the methoctramine structure, it is possible to design polyamine derivatives highly cytotoxic against tumor cells and that the appropriate design of molecules bearing polyamine-like structures leads to powerful inducers of autophagy. (C) 2013 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.06.044

文献信息

• In vitro and in vivo evaluation of polymethylene tetraamine derivatives as NMDA receptor channel blockers
  作者：Ryotaro Saiki、Yuki Yoshizawa、Anna Minarini、Andrea Milelli、Chiara Marchetti、Vincenzo Tumiatti、Toshihiko Toida、Keiko Kashiwagi、Kazuei Igarashi

  DOI：10.1016/j.bmcl.2013.04.063

  日期：2013.7

  The biological activities of six symmetrically substituted 2-methoxy-benzyl polymethylene tetraamines (1-4) and diphenylethyl polymethylene tetraamines (5 and 6) as N-methyl-D-aspartate (NMDA) receptor channel blockers, were evaluated in vitro and in vivo. Although all compounds exhibited stronger channel block activities in comparison to memantine in Xenopus oocytes voltage clamped at -70 mV, only compound 2 (0.4 mg/kg intravenous injection) decreased the size of brain infarction in a photochemically induced thrombosis model mice at the same extent of memantine (10 mg/kg intravenous injection). Other compounds (1, 3, 4, 5 and 6) did not decrease the size of brain infarction significantly due to the limited injection doses. The present study suggests that compound 2 could represent a valuable lead compound to design low toxicity polyamines for clinical use against stroke. (c) 2013 Elsevier Ltd. All rights reserved.
• Synthetic polyamines activating autophagy: Effects on cancer cell death
  作者：Anna Minarini、Maddalena Zini、Andrea Milelli、Vincenzo Tumiatti、Chiara Marchetti、Benedetta Nicolini、Mirella Falconi、Giovanna Farruggia、Concettina Cappadone、Claudio Stefanelli

  DOI：10.1016/j.ejmech.2013.06.044

  日期：2013.9

  The ability of symmetrically substituted long chain polymethylene tetramines, methoctramine (1) and its analogs 2-4 to kill cancer cells was studied. We found that an elevated cytotoxicity was correlated with a 12 methylene chain length separating the inner amine functions (6-12-6 carbon backbone), together with the introduction of diphenylethyl moieties on the terminal nitrogen atoms (compound 4) of a tetramine backbone. Compound 4 triggered dissipation of mitochondrial transmembrane potential and increased intracellular peroxide levels, leading to a caspase-independent HeLa cell death associated with a rapid activation of autophagy. The antioxidant N-acetylcysteine inhibited cell death and activation of autophagy, indicating a link between oxidative stress and autophagy. Autophagy was rapidly triggered even by tetramines 2 and 3, indicating that is related to their polyamine structure. Autophagy did not protect HeLa cells against cytotoxicity elicited by compound 4. The present study shows that, by modifications of the methoctramine structure, it is possible to design polyamine derivatives highly cytotoxic against tumor cells and that the appropriate design of molecules bearing polyamine-like structures leads to powerful inducers of autophagy. (C) 2013 Elsevier Masson SAS. All rights reserved.
• Differential blockade of muscarinic receptor subtypes by polymethylene tetraamines. Novel class of selective antagonists of cardiac M-2 muscarinic receptors
  作者：Carlo Melchiorre、Anna Cassinelli、Wilma Quaglia

  DOI：10.1021/jm00384a034

  日期：1987.1

  Several N,N'-bis[6-[(2-methoxybenzyl)amino]hexyl]-1, omega-alkanediamine tetrahydrochlorides were synthesized and evaluated for their blocking activity on muscarinic receptors in guinea pig atria and rat ileum and bladder. The results were compared with those obtained for the classical nonselective muscarinic antagonist atropine. It was discovered that optimum activity is associated with an eight-carbon chain (compound 4) in guinea pig atria whereas, in both rat ileum and bladder, the 12-carbon analogue 7 had the highest activity. In addition, polymethylene tetraamines 1-6 displayed high selectivity toward guinea pig atria muscarinic receptors. The discriminatory power of 1-6 was not shared by 7. All the tetraamines were shown to be competitive antagonists of muscarinic receptors. N,N'-Bis[6-[(2-methoxybenzyl)amino]hexyl]-1,8-octanediamine was the most potent and selective toward muscarinic receptors in atria, with a pA2 value of 8.13 and a selectivity ratio (atria vs. ileum or bladder) of ca. 270. At a concentration of 10 microM, tetraamine 4 did not affect histamine and 5-hydroxytryptamine receptors of guinea pig ileum or alpha-adrenoreceptors of guinea pig atria whereas it inhibited postsynaptic alpha-adrenoreceptors of rat vas deferens with a -log K value of 5.23 and nicotinic receptors of frog rectus abdominis with an IC50 value of 0.23 microM. It is concluded that 4 is a novel, powerful, and selective tool in the characterization of muscarinic receptor subtypes.