N-(3-aminopropyl)-N'-(3-ethylaminopropyl)butane-1,4-diamine

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: N-(3-aminopropyl)-N'-(3-ethylaminopropyl)butane-1,4-diamine
• 英文别名: N¹-ethylspermine；EtSPM；N1-ethylspermine；(Ethyl)spermine；N-(3-aminopropyl)-N'-[3-(ethylamino)propyl]butane-1,4-diamine
• 化学式: C₁₂H₃₀N₄
• 分子量: 230.397
• InChiKey: GMPAHNFBSGCUHV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.2
• 重原子数：
  16
• 可旋转键数：
  13
• 环数：
  0.0
• sp3杂化的碳原子比例：
  1.0
• 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：

  N-(3-aminopropyl)-N'-(3-ethylaminopropyl)butane-1,4-diamine 在 spermine 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：

  N¹-acetylspermine trihydrochloride 在 lithium aluminium tetrahydride 作用下， 以 四氢呋喃 为溶剂， 反应 12.0h， 生成 N-(3-aminopropyl)-N'-(3-ethylaminopropyl)butane-1,4-diamine
  参考文献：
  名称：

  Antiproliferative Properties of Polyamine Analogs: A Structure-Activity Study

  摘要：

  A basis set of polyamine analogues was designed and synthesized. These compounds were used to initiate a systematic investigation of the role of chain length, terminal nitrogen alkyl group size, and symmetry of the methylene backbone in the antineoplastic properties of polyamine analogues. New synthetic methods predicated on our earlier polyamine fragment synthesis are described for accessing the tetraamines of interest. An unsymmetrically substituted diamine reagent, N-(tert-butoxycarbonyl)-N,N'-bis(mesitylene sulfonyl)-1,4- di-aminobutane, was developed for entry into unsymmetrical tetraamines. All of the tetraamines synthesized were first evaluated in a murine leukemia L1210 cell IC50 assay at 48 and 96 h. In an attempt to correlate this behavior with some aspect of polyamine metabolism, each compound was tested for its ability to compete with spermidine for the polyamine uptake apparatus, its impact on the polyamine biosynthetic enzymes ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AdoMetDC), and its effect on the polyamine-catabolizing enzyme spermidine/spermine N-1-acetyltransferase (SSAT) and on polyamine pools. While there was no obvious correlation between the 48 and 96 h IC50'S and the impact of the analogues on polyamine metabolism, there were other structure-activity relationships. Correlations were observed to exist between chain length and IC50'S and between terminal alkyl substituents and impact on K-i, ODC, and AdoMetDC. Also, preliminary studies suggest a relationship may exist between the 48 and 96 h IC50's activities and the analogue's chronic toxicity in vivo. Finally, when the overall length of the polyamine backbone was held constant, the symmetry of the methylene chains of the polyamine fragments was shown to be unimportant to the compound's activity.

  DOI：

  10.1021/jm00047a004

文献信息

• C-10 CARBAMATES OF TAXANES
  申请人：Ballatore Carlo

  公开号：US20090306014A1

  公开（公告）日：2009-12-10

  Provided herein are C-10 taxane carbamates and pharmaceutically acceptable derivatives thereof. In certain embodiments, provided herein are compounds, compositions and methods for treating cancer and taupathy.

  本文提供了C-10紫杉烷氨甲酸酯及其药学上可接受的衍生物。在某些实施方式中，提供了化合物、组合物和治疗癌症和tau病理的方法。
• Novel polyamine analogues as therapeutic and diagnostic agents
  申请人：ORIDIGM CORPORATION

  公开号：EP1085011A1

  公开（公告）日：2001-03-21

  Novel inhibitors of polyamine transport having inhibition constants two orders of magnitude lower than those of known compounds are disclosed. These polyamine analogues are useful pharmaceutical agents for treating disease where it is desired to inhibit polyamine transport or other polyamine binding proteins, for example cancer and post-angioplasty injury. Novel chemical synthetic methods to obtain polyamine analogues are disclosed, including the production of a combinatorial polyamine library. These approaches yield analogues with desirable activities both for diagnostic and research assays and therapy. The assays of the invention are useful for high throughput screening of targets in the discovery of drugs that interact with the polyamine system.

  本发明揭示了具有比已知化合物低两个数量级的抑制常数的多胺转运抑制剂。这些多胺类似物是治疗需要抑制多胺转运或其他多胺结合蛋白的疾病的有用药物，例如癌症和血管成形术后的损伤。揭示了获得多胺类似物的新的化学合成方法，包括制备组合多胺库。这些方法产生的类似物具有理想的诊断和研究测定和治疗活性。本发明的测定方法对于高通量筛选与多胺系统相互作用的药物发现目标非常有用。
• [EN] NOVEL POLYAMINE ANALOG CONJUGATES AND QUINONE CONJUGATES AS THERAPIES FOR CANCERS AND PROSTATE DISEASES<br/>[FR] NOUVEAUX CONJUGUES D'ANALOGUE DE POLYAMINE ET CONJUGUES DE QUINONE, UTILISES POUR LE TRAITEMENT DE CANCERS ET DE MALADIES DE LA PROSTATE
  申请人：SLIL BIOMEDICAL CORP

  公开号：WO2000066175A2

  公开（公告）日：2000-11-09

  Peptide conjugates in which cytocidal and cytostatic agents, such as polyamine analogs or naphthoquinones, are conjugated to a polypeptide recognized and cleaved by enzymes such as prostate-specific antigen (PSA) and cathepsin B are provided, as well as compositions comprising these conjugates. Methods of using these conjugates in the treatment of prostate diseases are also provided.

  提供一种肽共轭物，其中将细胞毒性和细胞增殖抑制剂，如多胺类似物或萘醌类化合物，与多肽共轭，该多肽可以被酶如前列腺特异性抗原（PSA）和半胱氨酸蛋白酶B识别和剪切，以及包含这些共轭物的组合物。还提供了使用这些共轭物治疗前列腺疾病的方法。
• Polyamine-metal chelator conjugates
  申请人：Bergeron J. Raymond

  公开号：US20060211773A1

  公开（公告）日：2006-09-21

  Many metal collators have polar or charged functional groups, which render them difficult to transport across a cell membrane. Polyimide-metal collator conjugates of the invention are compounds comprising a first moiety which is a metal collator and a second moiety which is a polyimide, where the polyimide moiety includes three or more nitrogen atoms which are capable of being positively charged at physiological pH. A sperms-L1 conjugate has been shown to accumulate in L1210 cells several hundred fold more than the unconjugated L1 chelator.

  许多金属配体具有极性或带电的功能基团，这使它们难以穿过细胞膜。本发明的聚酰亚胺-金属配体共轭物是由第一部分为金属配体，第二部分为聚酰亚胺的化合物组成，其中聚酰亚胺部分包含三个或更多的氮原子，在生理pH下能够呈正电荷。已经证明，精子-L1共轭物在L1210细胞中的积累量比未共轭的L1螯合剂高出数百倍。
• Polyamine-Metal Chelator Conjugates
  申请人：Bergeron Raymond

  公开号：US20080096974A2

  公开（公告）日：2008-04-24

  Many metal chelators have polar or charged functional groups, which render them difficult to transport across a cell membrane. Polyamine-metal chelator conjugates of the invention are compounds comprising a first moiety which is a metal chelator and a second moiety which is a polyamine, where the polyamine moiety includes three or more nitrogen atoms which are capable of being positively charged at physiological pH. A spermine-L1 conjugate has been shown to accumulate in L1210 cells several hundred fold more than the unconjugated L1 chelator.

  许多金属螯合剂具有极性或带电的功能基团，这使得它们难以跨越细胞膜。本发明的多胺-金属螯合剂共轭物是化合物，包括第一部分是金属螯合剂，第二部分是多胺，其中多胺部分包括三个或更多的氮原子，在生理pH下能够呈正电荷。已经证明精胺-L1共轭物在L1210细胞中的积累比未共轭的L1螯合剂高出数百倍。