N¹-(3-aminopropyl)-N⁴-(3-(benzylamino)propyl)butane-1,4-diamine

• 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: N¹-(3-aminopropyl)-N⁴-(3-(benzylamino)propyl)butane-1,4-diamine
• 英文别名: N¹-benzylspermine；N-(3-aminopropyl)-N'-(3-benzylaminopropyl)butane-1,4-diamine；BnSPM；N-(3-amino-propyl)-N'-(3-benzylamino-propyl)-butane-1,4-diamine；N-(3-aminopropyl)-N'-[3-(benzylamino)propyl]butane-1,4-diamine
• 化学式: C₁₇H₃₂N₄
• 分子量: 292.468
• InChiKey: BXEVLOZJWSSRDM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  21
• 可旋转键数：
  14
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  62.1
• 氢给体数：
  4
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N¹-(3-aminopropyl)-N⁴-(3-(benzylamino)propyl)butane-1,4-diamine 在 recombinant human polyamine oxidase 作用下， 生成 亚精胺
  参考文献：
  名称：

  Metabolism of N-alkylated spermine analogues by polyamine and spermine oxidases

  摘要：

  N-alkylated polyamine analogues have potential as anticancer and antiparasitic drugs. However, their metabolism in the host has remained incompletely defined thus potentially limiting their utility. Here, we have studied the degradation of three different spermine analogues N,N'-bis-(3-ethylaminopropyl)butane-1,4-diamine (DESPM), N-(3-benzyl-aminopropyl)-N'-(3-ethylaminopropyl)butane-1,4-diamine (BnEtSPM) and N,N'-bis-(3-benzylaminopropyl)butane-1,4-diamine (DBSPM) and related mono-alkylated derivatives as substrates of recombinant human polyamine oxidase (APAO) and spermine oxidase (SMO). APAO and SMO metabolized DESPM to EtSPD [K (m(APAO)) = 10 mu M, k (cat(APAO)) = 1.1 s(-1) and K (m(SMO)) = 28 mu M, k (cat(SMO)) = 0.8 s(-1), respectively], metabolized BnEtSPM to EtSPD [K (m(APAO)) = 0.9 mu M, k (cat(APAO)) = 1.1 s(-1) and K (m(SMO)) = 51 mu M, k (cat(SMO)) = 0.4 s(-1), respectively], and metabolized DBSPM to BnSPD [K (m(APAO)) = 5.4 mu M, k (cat(APAO)) = 2.0 s(-1) and K (m(SMO)) = 33 mu M, k (cat(SMO)) = 0.3 s(-1), respectively]. Interestingly, mono-alkylated spermine derivatives were metabolized by APAO and SMO to SPD [EtSPM K (m(APAO)) = 16 mu M, k (cat(APAO)) = 1.5 s(-1); K (m(SMO)) = 25 mu M, k (cat(SMO)) = 8.2 s(-1); BnSPM K (m(APAO)) = 6.0 mu M, k (cat(APAO)) = 2.8 s(-1); K (m(SMO)) = 19 mu M, k (cat(SMO)) = 0.8 s(-1), respectively]. Surprisingly, EtSPD [K (m(APAO)) = 37 mu M, k (cat(APAO)) = 0.1 s(-1); K (m(SMO)) = 48 mu M, k (cat(SMO)) = 0.05 s(-1)] and BnSPD [K (m(APAO)) = 2.5 mu M, k (cat(APAO)) = 3.5 s(-1); K (m(SMO)) = 60 mu M, k (cat(SMO)) = 0.54 s(-1)] were metabolized to SPD by both the oxidases. Furthermore, we studied the degradation of DESPM, BnEtSPM or DBSPM in the DU145 prostate carcinoma cell line. The same major metabolites EtSPD and/or BnSPD were detected both in the culture medium and intracellularly after 48 h of culture. Moreover, EtSPM and BnSPM were detected from cell samples. Present data shows that inducible SMO parallel with APAO could play an important role in polyamine based drug action, i.e. degradation of parent drug and its metabolites, having significant impact on efficiency of these drugs, and hence for the development of novel N-alkylated polyamine analogues.

  DOI：

  10.1007/s00726-009-0429-2
• 作为产物：
  描述：

  N(1)-benzyl-N(1),N(3)-bis(2-nitrobenzenesulfonyl)propane-1,3-diamine 在 recombinant human polyamine oxidase 作用下， 生成 N¹-(3-aminopropyl)-N⁴-(3-(benzylamino)propyl)butane-1,4-diamine
  参考文献：
  名称：

  Metabolism of N-alkylated spermine analogues by polyamine and spermine oxidases

  摘要：

  N-alkylated polyamine analogues have potential as anticancer and antiparasitic drugs. However, their metabolism in the host has remained incompletely defined thus potentially limiting their utility. Here, we have studied the degradation of three different spermine analogues N,N'-bis-(3-ethylaminopropyl)butane-1,4-diamine (DESPM), N-(3-benzyl-aminopropyl)-N'-(3-ethylaminopropyl)butane-1,4-diamine (BnEtSPM) and N,N'-bis-(3-benzylaminopropyl)butane-1,4-diamine (DBSPM) and related mono-alkylated derivatives as substrates of recombinant human polyamine oxidase (APAO) and spermine oxidase (SMO). APAO and SMO metabolized DESPM to EtSPD [K (m(APAO)) = 10 mu M, k (cat(APAO)) = 1.1 s(-1) and K (m(SMO)) = 28 mu M, k (cat(SMO)) = 0.8 s(-1), respectively], metabolized BnEtSPM to EtSPD [K (m(APAO)) = 0.9 mu M, k (cat(APAO)) = 1.1 s(-1) and K (m(SMO)) = 51 mu M, k (cat(SMO)) = 0.4 s(-1), respectively], and metabolized DBSPM to BnSPD [K (m(APAO)) = 5.4 mu M, k (cat(APAO)) = 2.0 s(-1) and K (m(SMO)) = 33 mu M, k (cat(SMO)) = 0.3 s(-1), respectively]. Interestingly, mono-alkylated spermine derivatives were metabolized by APAO and SMO to SPD [EtSPM K (m(APAO)) = 16 mu M, k (cat(APAO)) = 1.5 s(-1); K (m(SMO)) = 25 mu M, k (cat(SMO)) = 8.2 s(-1); BnSPM K (m(APAO)) = 6.0 mu M, k (cat(APAO)) = 2.8 s(-1); K (m(SMO)) = 19 mu M, k (cat(SMO)) = 0.8 s(-1), respectively]. Surprisingly, EtSPD [K (m(APAO)) = 37 mu M, k (cat(APAO)) = 0.1 s(-1); K (m(SMO)) = 48 mu M, k (cat(SMO)) = 0.05 s(-1)] and BnSPD [K (m(APAO)) = 2.5 mu M, k (cat(APAO)) = 3.5 s(-1); K (m(SMO)) = 60 mu M, k (cat(SMO)) = 0.54 s(-1)] were metabolized to SPD by both the oxidases. Furthermore, we studied the degradation of DESPM, BnEtSPM or DBSPM in the DU145 prostate carcinoma cell line. The same major metabolites EtSPD and/or BnSPD were detected both in the culture medium and intracellularly after 48 h of culture. Moreover, EtSPM and BnSPM were detected from cell samples. Present data shows that inducible SMO parallel with APAO could play an important role in polyamine based drug action, i.e. degradation of parent drug and its metabolites, having significant impact on efficiency of these drugs, and hence for the development of novel N-alkylated polyamine analogues.

  DOI：

  10.1007/s00726-009-0429-2

文献信息

• Solid phase organic synthesis of polyamine derivatives and initial biological evaluation of their antitumoral activity
  作者：Sophie Tomasi、Myriam Le Roch、Jacques Renault、Jean-Charles Corbel、Philippe Uriac、Bertrand Carboni、Damien Moncoq、Bénedicte Martin、Jean-Guy Delcros

  DOI：10.1016/s0960-894x(98)00086-9

  日期：1998.3

  A series of N-1-monosubstituted putrescine and spermine derivatives was synthesised using a solid phase methodology. We evaluated their cytotoxicity, calmodulin antagonism and polyamine uptake inhibition, pharmacological. properties shared by some antitumoral agents. (C) 1998 Elsevier Science Ltd. All rights reserved.
• Metabolism of N-alkylated spermine analogues by polyamine and spermine oxidases
  作者：Merja R. Häkkinen、Mervi T. Hyvönen、Seppo Auriola、Robert A. Casero、Jouko Vepsäläinen、Alex R. Khomutov、Leena Alhonen、Tuomo A. Keinänen

  DOI：10.1007/s00726-009-0429-2

  日期：2010.2

  N-alkylated polyamine analogues have potential as anticancer and antiparasitic drugs. However, their metabolism in the host has remained incompletely defined thus potentially limiting their utility. Here, we have studied the degradation of three different spermine analogues N,N'-bis-(3-ethylaminopropyl)butane-1,4-diamine (DESPM), N-(3-benzyl-aminopropyl)-N'-(3-ethylaminopropyl)butane-1,4-diamine (BnEtSPM) and N,N'-bis-(3-benzylaminopropyl)butane-1,4-diamine (DBSPM) and related mono-alkylated derivatives as substrates of recombinant human polyamine oxidase (APAO) and spermine oxidase (SMO). APAO and SMO metabolized DESPM to EtSPD [K (m(APAO)) = 10 mu M, k (cat(APAO)) = 1.1 s(-1) and K (m(SMO)) = 28 mu M, k (cat(SMO)) = 0.8 s(-1), respectively], metabolized BnEtSPM to EtSPD [K (m(APAO)) = 0.9 mu M, k (cat(APAO)) = 1.1 s(-1) and K (m(SMO)) = 51 mu M, k (cat(SMO)) = 0.4 s(-1), respectively], and metabolized DBSPM to BnSPD [K (m(APAO)) = 5.4 mu M, k (cat(APAO)) = 2.0 s(-1) and K (m(SMO)) = 33 mu M, k (cat(SMO)) = 0.3 s(-1), respectively]. Interestingly, mono-alkylated spermine derivatives were metabolized by APAO and SMO to SPD [EtSPM K (m(APAO)) = 16 mu M, k (cat(APAO)) = 1.5 s(-1); K (m(SMO)) = 25 mu M, k (cat(SMO)) = 8.2 s(-1); BnSPM K (m(APAO)) = 6.0 mu M, k (cat(APAO)) = 2.8 s(-1); K (m(SMO)) = 19 mu M, k (cat(SMO)) = 0.8 s(-1), respectively]. Surprisingly, EtSPD [K (m(APAO)) = 37 mu M, k (cat(APAO)) = 0.1 s(-1); K (m(SMO)) = 48 mu M, k (cat(SMO)) = 0.05 s(-1)] and BnSPD [K (m(APAO)) = 2.5 mu M, k (cat(APAO)) = 3.5 s(-1); K (m(SMO)) = 60 mu M, k (cat(SMO)) = 0.54 s(-1)] were metabolized to SPD by both the oxidases. Furthermore, we studied the degradation of DESPM, BnEtSPM or DBSPM in the DU145 prostate carcinoma cell line. The same major metabolites EtSPD and/or BnSPD were detected both in the culture medium and intracellularly after 48 h of culture. Moreover, EtSPM and BnSPM were detected from cell samples. Present data shows that inducible SMO parallel with APAO could play an important role in polyamine based drug action, i.e. degradation of parent drug and its metabolites, having significant impact on efficiency of these drugs, and hence for the development of novel N-alkylated polyamine analogues.