N¹,N⁴,N⁸,N¹¹-tetrakis(mesitylenesulfonyl)-N¹-ethylnorspermine | 151915-13-8

• 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: N¹,N⁴,N⁸,N¹¹-tetrakis(mesitylenesulfonyl)-N¹-ethylnorspermine
• 英文别名: 1-<amino>-4,8-bis-11-amino-4,8-diazaundecane；N-[3-[3-[3-[ethyl-(2,4,6-trimethylphenyl)sulfonylamino]propyl-(2,4,6-trimethylphenyl)sulfonylamino]propyl-(2,4,6-trimethylphenyl)sulfonylamino]propyl]-2,4,6-trimethylbenzenesulfonamide
• CAS: 151915-13-8
• 化学式: C₄₇H₆₈N₄O₈S₄
• 分子量: 945.343
• InChiKey: KXHNXHKNSUGSDQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  9.2
• 重原子数：
  63
• 可旋转键数：
  21
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.49
• 拓扑面积：
  192
• 氢给体数：
  1
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  N¹,N⁴,N⁸,N¹¹-tetrakis(mesitylenesulfonyl)-N¹-ethylnorspermine 在 氢溴酸 、 sodium hydride 、 溶剂黄146 、 苯酚 作用下， 以 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 15.5h， 生成 (S)-1--11-(N-ethylamino)-4,8-diazaundecane tetrahydrobromide
  参考文献：
  名称：

  1-(N-Alkylamino)-11-(N-ethylamino)-4,8-diazaundecanes:  Simple Synthetic Polyamine Analogues That Differentially Alter Tubulin Polymerization

  摘要：

  Polyamine analogues such as bis(ethyl)norspermine and N-1-(cyclopropylmethyl)-N-11-ethyl-4,8-diazaundecane (CPENSpm) act as potent modulators of cellular polyamine metabolism in vitro and possess impressive antitumor activity against a number of cell lines. Some of these polyamine analogues appear to produce their cell-type-specific cytotoxic activity through the superinduction of spermidine/spermine N-1-acetyltransferase (SSAT). However, there are several analogues (e.g., N-1-(cycloheptylmethyl)-N-11-ethyl-4,8-diazaundecane (CHENSpm)) which are effective cytotoxic agents but do not superinduce SSAT. We have previously demonstrated that CPENSpm and CHENSpm both initiate the cell death program, although by different mechanisms, and that CHENSpm (but not CPENSpm) induces a G(2)/M cell cycle arrest. We now report that one potential mechanism by which some polyamine analogues can retard growth and ultimately produce cytotoxicity is through interference with normal tubulin polymerization. In these studies, we compare the effects of the polyamine analogues CHENSpm, CPENSpm, and (S)-N-1-(2-methyl-1-butyl)-N-11-ethyl-4,8-diazaundecane (IPENSpm) on in vitro tubulin polymerization. These spermine analogues behave very differently from spermine and from each other in terms of tubulin polymerization rate, equilibrium levels, and time of polymerization initiation. These results demonstrate that structurally similar polyamine analogues with potent antitumor effects can produce significantly different cellular effects. The discovery of polyamine analogues that can alter tubulin polymerization provides a series of promising lead compounds that: may have a similar spectrum of activity to more difficult to synthesize compounds typified by paclitaxel.

  DOI：

  10.1021/jm980603+
• 作为产物：
  描述：

  2,4,6-三甲基苯磺酰氯 在 palladium on activated charcoal sodium hydroxide 、 氢气 、 sodium hydride 、 肼 作用下， 以 甲醇 、 二氯甲烷 、 氯仿 、 N,N-二甲基甲酰胺 为溶剂， 50.0 ℃ 、344.73 kPa 条件下， 反应 79.5h， 生成 N¹,N⁴,N⁸,N¹¹-tetrakis(mesitylenesulfonyl)-N¹-ethylnorspermine
  参考文献：
  名称：

  合成和评估不对称取代的多胺类似物作为人类亚精胺/亚精胺-N1-乙酰基转移酶（SSAT）的调节剂并作为潜在的抗肿瘤药。

  摘要：

  亚胺/亚精胺-N1-乙酰基转移酶（SSAT）是多胺分解代谢中的限速步骤，对细胞多胺的相互转化和调节至关重要。抑制剂引发的这种酶的诱导也似乎与肿瘤细胞对一类新型多胺类似物双（乙基）多胺的敏感性相关。因此，调节SSAT细胞水平的末端烷基化多胺对于理解该酶在类似物介导的细胞毒性和整个细胞多胺代谢中的作用可能具有重要价值。此类类似物还可通过破坏细胞多胺代谢而成为重要的治疗剂。尚未完全阐明定义多胺类似物与SSAT相互作用的结构活性关系，特别是，尚未合成不对称的烷基化多胺并将其评估为SSAT的调节剂。为此，我们现在通过合成途径报告N1-乙基-N11-炔丙基-4,8-​​二氮杂十二烷和N1-乙基-N11-（（环丙基）甲基）-4,8-​​二氮杂十一烷的合成和初步生物学评估它代表了通往各种不对称取代的多胺类似物的有效途径。标题化合物充当分离的人SSAT的有效抑制剂，并在原位产生SSAT的差异超诱导，这似乎与

  DOI：

  10.1021/jm00072a020

文献信息

• Synthesis and evaluation of unsymmetrically substituted polyamine analogs as modulators of human spermidine/spermine-N1-acetyltransferase (SSAT) and as potential antitumor agents
  作者：Nada H. Saab、Edward E. West、Nella C. Bieszk、Charles V. Preuss、Amy R. Mank、Robert A. Casero、Patrick M. Woster

  DOI：10.1021/jm00072a020

  日期：1993.10

  analogue-mediated cytotoxicity and in overall cellular polyamine metabolism. Such analogues could also become important therapeutic agents by disrupting cellular polyamine metabolism. The structure-activity relationships defining the interaction of polyamine analogues with SSAT have not been fully elucidated, and, in particular, unsymmetrically alkylated polyamines have not been synthesized and evaluated as modulators

  亚胺/亚精胺-N1-乙酰基转移酶（SSAT）是多胺分解代谢中的限速步骤，对细胞多胺的相互转化和调节至关重要。抑制剂引发的这种酶的诱导也似乎与肿瘤细胞对一类新型多胺类似物双（乙基）多胺的敏感性相关。因此，调节SSAT细胞水平的末端烷基化多胺对于理解该酶在类似物介导的细胞毒性和整个细胞多胺代谢中的作用可能具有重要价值。此类类似物还可通过破坏细胞多胺代谢而成为重要的治疗剂。尚未完全阐明定义多胺类似物与SSAT相互作用的结构活性关系，特别是，尚未合成不对称的烷基化多胺并将其评估为SSAT的调节剂。为此，我们现在通过合成途径报告N1-乙基-N11-炔丙基-4,8-​​二氮杂十二烷和N1-乙基-N11-（（环丙基）甲基）-4,8-​​二氮杂十一烷的合成和初步生物学评估它代表了通往各种不对称取代的多胺类似物的有效途径。标题化合物充当分离的人SSAT的有效抑制剂，并在原位产生SSAT的差异超诱导，这似乎与
• Antiproliferative Properties of Polyamine Analogs: A Structure-Activity Study
  作者：Raymond J. Bergeron、James S. McManis、Charles Z. Liu、Yang Feng、William R. Weimar、Gabriel R. Luchetta、Qianhong Wu、Jackqueline Ortiz-Ocasio、J. R. Timothy Vinson

  DOI：10.1021/jm00047a004

  日期：1994.10

  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.
• 1-(<i>N</i>-Alkylamino)-11-(<i>N</i>-ethylamino)-4,8-diazaundecanes:  Simple Synthetic Polyamine Analogues That Differentially Alter Tubulin Polymerization
  作者：Heather K. Webb、Zhiqian Wu、Nilantha Sirisoma、Hyo Chol Ha、Robert A. Casero,、Patrick M. Woster

  DOI：10.1021/jm980603+

  日期：1999.4.22

  Polyamine analogues such as bis(ethyl)norspermine and N-1-(cyclopropylmethyl)-N-11-ethyl-4,8-diazaundecane (CPENSpm) act as potent modulators of cellular polyamine metabolism in vitro and possess impressive antitumor activity against a number of cell lines. Some of these polyamine analogues appear to produce their cell-type-specific cytotoxic activity through the superinduction of spermidine/spermine N-1-acetyltransferase (SSAT). However, there are several analogues (e.g., N-1-(cycloheptylmethyl)-N-11-ethyl-4,8-diazaundecane (CHENSpm)) which are effective cytotoxic agents but do not superinduce SSAT. We have previously demonstrated that CPENSpm and CHENSpm both initiate the cell death program, although by different mechanisms, and that CHENSpm (but not CPENSpm) induces a G(2)/M cell cycle arrest. We now report that one potential mechanism by which some polyamine analogues can retard growth and ultimately produce cytotoxicity is through interference with normal tubulin polymerization. In these studies, we compare the effects of the polyamine analogues CHENSpm, CPENSpm, and (S)-N-1-(2-methyl-1-butyl)-N-11-ethyl-4,8-diazaundecane (IPENSpm) on in vitro tubulin polymerization. These spermine analogues behave very differently from spermine and from each other in terms of tubulin polymerization rate, equilibrium levels, and time of polymerization initiation. These results demonstrate that structurally similar polyamine analogues with potent antitumor effects can produce significantly different cellular effects. The discovery of polyamine analogues that can alter tubulin polymerization provides a series of promising lead compounds that: may have a similar spectrum of activity to more difficult to synthesize compounds typified by paclitaxel.