(6R,15R)-3,8,13,18-tetraazaicosane-6,15-diol | 245107-51-1

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: (6R,15R)-3,8,13,18-tetraazaicosane-6,15-diol
• 英文别名: (2R)-4-(ethylamino)-1-[4-[[(2R)-4-(ethylamino)-2-hydroxybutyl]amino]butylamino]butan-2-ol
• CAS: 245107-51-1
• 化学式: C₁₆H₃₈N₄O₂
• 分子量: 318.503
• InChiKey: AFXLPCNTPZQBIC-HZPDHXFCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.6
• 重原子数：
  22
• 可旋转键数：
  17
• 环数：
  0.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  88.6
• 氢给体数：
  6
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (6R,15R)-3,8,13,18-tetraazaicosane-6,15-diol 在 吡啶 、 potassium hydrogencarbonate 作用下， 以 四氯化碳 、 乙醚 为溶剂， 反应 22.0h， 生成 (3R,12R)-3,12-bis[(S)-α-methoxy-α-(trifluoromethyl)phenylacetoxy]-N¹,N¹⁴-diethyl-N¹,N⁵,N¹⁰,N¹⁴-tetrakis(benzyloxycarbonyl)norspermine
  参考文献：
  名称：

  Synthesis and Evaluation of Hydroxylated Polyamine Analogues as Antiproliferatives

  摘要：

  The synthesis of four hydroxylated polyamine analogues, (2R,10R)-N-1,N-11-diethyl-2,10-dihydroxynorspermine, droxynorspermine, (2S,10S)-N-1,N-11-diethyl-2,10-dihydroxynospermine, (3S, 12S)-N-1,N-14-diethyl-3, 12-dihydroyhomospermine, and (3R,12R)-N-1-N-14-diethyl-3,12-dihgrdroxyhomospermine, is described along with their impact on the growth and polyamine metabolism of L1210 murine leukemia cells. Four different synthetic approaches are set forth, two each for the hydroxylated norspermines and for the hydroxylated homospermines. The key step in the assembly of the norspermines was the coupling of either N-[2R)-2,3-epoxypropyl]-N-ethyl p-toluenesulfonamide or N-[(2S)-2, 3-epoxypropyl]-N-ethyl trifluoromethane sulfonamide to N,N'-dibenzyl-1,3-diaminopropane. The key step with homospermines employed alkylation of putrescine with (3S)-N-(benzyloxycarbonyl)-N-ethyl-3,4-epoxybutylamine or of N,N'-bis(mesitylenesulfonyl)-1,4-butanediamine with (2R)-2-benzyloxy-4-[N-(mesitylenesulfonyl], All of the hydroxylated analogues were active against L1210 cells with 96-h IC50 values of less than or equal to 2 mu M, and they also effectively reduced putrescine and spermidine, although the effect on spermine pools ranged from moderate to insignificant. Interestingly, the impact of the hydroxylated analogues an ornithine decarboxylase (ODC) was significantly less than that of unhydroxylated parent drug (e.g., (NN11)-N-1-diethylnorspermine [DENSPM]) at 1 mu M ; however, S-adenosylmethionine decarboxylase (AdoMetDC) depletion was nearly identical to what was observed in cells treated with parent drug. The most notable difference between the parent and hydroxylated analogues was seen with spermidine/spermine N-1-acetyltransferase (SSAT) upregulation in the DENSPM series. The hydroxylated analogues, especially (R,R)-(HO)(2)-DENSPM, were much less effective at upregulation than the parent DENSPM. Finally, a comparison of the toxicity of (RP)-(HO)(2)DENSPM with that of DENSPM at subchronic doses revealed that the neurological effects seen with DENSPM were now absent.

  DOI：

  10.1021/jm990375z
• 作为产物：
  描述：

  (3R,12R)-dibenzyloxy-N¹,N¹⁴-diethyl-N¹,N⁵,N¹⁰,N¹⁴-tetrakis(mesitylenesulfonyl)homospermine 在 钯 氢气 、 sodium naphthalenide 、 溶剂黄146 作用下， 以 乙二醇二甲醚 为溶剂， -78.0~20.0 ℃ 、101.33 kPa 条件下， 生成 (6R,15R)-3,8,13,18-tetraazaicosane-6,15-diol
  参考文献：
  名称：

  Synthesis and Evaluation of Hydroxylated Polyamine Analogues as Antiproliferatives

  摘要：

  The synthesis of four hydroxylated polyamine analogues, (2R,10R)-N-1,N-11-diethyl-2,10-dihydroxynorspermine, droxynorspermine, (2S,10S)-N-1,N-11-diethyl-2,10-dihydroxynospermine, (3S, 12S)-N-1,N-14-diethyl-3, 12-dihydroyhomospermine, and (3R,12R)-N-1-N-14-diethyl-3,12-dihgrdroxyhomospermine, is described along with their impact on the growth and polyamine metabolism of L1210 murine leukemia cells. Four different synthetic approaches are set forth, two each for the hydroxylated norspermines and for the hydroxylated homospermines. The key step in the assembly of the norspermines was the coupling of either N-[2R)-2,3-epoxypropyl]-N-ethyl p-toluenesulfonamide or N-[(2S)-2, 3-epoxypropyl]-N-ethyl trifluoromethane sulfonamide to N,N'-dibenzyl-1,3-diaminopropane. The key step with homospermines employed alkylation of putrescine with (3S)-N-(benzyloxycarbonyl)-N-ethyl-3,4-epoxybutylamine or of N,N'-bis(mesitylenesulfonyl)-1,4-butanediamine with (2R)-2-benzyloxy-4-[N-(mesitylenesulfonyl], All of the hydroxylated analogues were active against L1210 cells with 96-h IC50 values of less than or equal to 2 mu M, and they also effectively reduced putrescine and spermidine, although the effect on spermine pools ranged from moderate to insignificant. Interestingly, the impact of the hydroxylated analogues an ornithine decarboxylase (ODC) was significantly less than that of unhydroxylated parent drug (e.g., (NN11)-N-1-diethylnorspermine [DENSPM]) at 1 mu M ; however, S-adenosylmethionine decarboxylase (AdoMetDC) depletion was nearly identical to what was observed in cells treated with parent drug. The most notable difference between the parent and hydroxylated analogues was seen with spermidine/spermine N-1-acetyltransferase (SSAT) upregulation in the DENSPM series. The hydroxylated analogues, especially (R,R)-(HO)(2)-DENSPM, were much less effective at upregulation than the parent DENSPM. Finally, a comparison of the toxicity of (RP)-(HO)(2)DENSPM with that of DENSPM at subchronic doses revealed that the neurological effects seen with DENSPM were now absent.

  DOI：

  10.1021/jm990375z

文献信息

• Synthesis and Evaluation of Hydroxylated Polyamine Analogues as Antiproliferatives
  作者：Raymond J. Bergeron、Ralf Müller、Jörg Bussenius、James S. McManis、Ronald L. Merriman、Richard E. Smith、Hua Yao、William R. Weimar

  DOI：10.1021/jm990375z

  日期：2000.1.1

  The synthesis of four hydroxylated polyamine analogues, (2R,10R)-N-1,N-11-diethyl-2,10-dihydroxynorspermine, droxynorspermine, (2S,10S)-N-1,N-11-diethyl-2,10-dihydroxynospermine, (3S, 12S)-N-1,N-14-diethyl-3, 12-dihydroyhomospermine, and (3R,12R)-N-1-N-14-diethyl-3,12-dihgrdroxyhomospermine, is described along with their impact on the growth and polyamine metabolism of L1210 murine leukemia cells. Four different synthetic approaches are set forth, two each for the hydroxylated norspermines and for the hydroxylated homospermines. The key step in the assembly of the norspermines was the coupling of either N-[2R)-2,3-epoxypropyl]-N-ethyl p-toluenesulfonamide or N-[(2S)-2, 3-epoxypropyl]-N-ethyl trifluoromethane sulfonamide to N,N'-dibenzyl-1,3-diaminopropane. The key step with homospermines employed alkylation of putrescine with (3S)-N-(benzyloxycarbonyl)-N-ethyl-3,4-epoxybutylamine or of N,N'-bis(mesitylenesulfonyl)-1,4-butanediamine with (2R)-2-benzyloxy-4-[N-(mesitylenesulfonyl], All of the hydroxylated analogues were active against L1210 cells with 96-h IC50 values of less than or equal to 2 mu M, and they also effectively reduced putrescine and spermidine, although the effect on spermine pools ranged from moderate to insignificant. Interestingly, the impact of the hydroxylated analogues an ornithine decarboxylase (ODC) was significantly less than that of unhydroxylated parent drug (e.g., (NN11)-N-1-diethylnorspermine [DENSPM]) at 1 mu M ; however, S-adenosylmethionine decarboxylase (AdoMetDC) depletion was nearly identical to what was observed in cells treated with parent drug. The most notable difference between the parent and hydroxylated analogues was seen with spermidine/spermine N-1-acetyltransferase (SSAT) upregulation in the DENSPM series. The hydroxylated analogues, especially (R,R)-(HO)(2)-DENSPM, were much less effective at upregulation than the parent DENSPM. Finally, a comparison of the toxicity of (RP)-(HO)(2)DENSPM with that of DENSPM at subchronic doses revealed that the neurological effects seen with DENSPM were now absent.