(4-{tert-Butoxycarbonyl-[3-(2-cyano-ethylamino)-propyl]-amino}-butyl)-[3-(2-cyano-ethylamino)-propyl]-carbamic acid tert-butyl ester | 861899-11-8

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (4-{tert-Butoxycarbonyl-[3-(2-cyano-ethylamino)-propyl]-amino}-butyl)-[3-(2-cyano-ethylamino)-propyl]-carbamic acid tert-butyl ester
• 英文别名: tert-butyl N-[3-(2-cyanoethylamino)propyl]-N-[4-[3-(2-cyanoethylamino)propyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]butyl]carbamate
• CAS: 861899-11-8
• 化学式: C₂₆H₄₈N₆O₄
• 分子量: 508.705
• InChiKey: AOWNGANUFXQAGS-UHFFFAOYSA-N

物化性质

• 沸点：
  652.0±55.0 °C(Predicted)
• 密度：
  1.051±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  36
• 可旋转键数：
  21
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.85
• 拓扑面积：
  131
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (4-{tert-Butoxycarbonyl-[3-(2-cyano-ethylamino)-propyl]-amino}-butyl)-[3-(2-cyano-ethylamino)-propyl]-carbamic acid tert-butyl ester 在 palladium dihydroxide 盐酸 、 氢气 、 溶剂黄146 、 三乙胺 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 44.5h， 生成 N1,N14-bis[N-dodecanylsulfonyl-3-aminopropyl]-1,14-diamino-5,10-diazabutadecane tetrahydrochloride
  参考文献：
  名称：

  Polycationic Sulfonamides for the Sequestration of Endotoxin

  摘要：

  Lipopolysaccharides (LPS) play a key role in the pathogenesis of septic shock, a major cause of mortality in the critically ill patient. We had previously shown that monoacylated polyamine compounds specifically bind to and neutralize the activity of LPS with high in vitro potency and afford complete protection in a murine model of endotoxic shock. Fatty acid amides of polyamines may be rapidly cleared from systemic circulation due to their susceptibility to nonspecific serum amidases and, thus, would be predicted to have a short duration of action. In a systematic effort to increase the likelihood of better bioavailability properties together with structural modifications that may result in gains in activity, we now report structure-activity relationships pertaining to endotoxin-binding and -neutralizing activities of homologated polyamine sulfonamides.

  DOI：

  10.1021/jm061198m
• 作为产物：
  描述：

  精胺 在 ammonium hydroxide 作用下， 以 甲醇 为溶剂， 反应 47.5h， 生成 (4-{tert-Butoxycarbonyl-[3-(2-cyano-ethylamino)-propyl]-amino}-butyl)-[3-(2-cyano-ethylamino)-propyl]-carbamic acid tert-butyl ester
  参考文献：
  名称：

  Lipopolysaccharide Sequestrants:  Structural Correlates of Activity and Toxicity in Novel Acylhomospermines

  摘要：

  Lipopolysaccharides (LPS), otherwise termed "endotoxins", are outer membrane constituents of Gram-negative bacteria. Lipopolysaccharides play a key role in the pathogenesis of "septic shock", a major cause of mortality in the critically ill patient. Therapeutic options aimed at limiting downstream systemic inflammatory processes by targeting lipopolysaccharide do not exist at the present time. We have defined the pharmacophore necessary for small molecules to specifically bind and neutralize LPS and, using animal models of sepsis, have shown that the sequestration of circulatory LPS by small molecules is a therapeutically viable strategy. In this paper, the interactions of a series of acylated homologated spermine compounds with LPS have been characterized. The optimal acyl chain length for effective sequestration of LPS was identified to be C-16 for the monoacyl compounds. The most promising of these compounds, 4e, binds LPS with an ED50 of 1.37 mu M. Nitric oxide production in murine J774A.1 cells, as well as TNF-alpha in human blood, is inhibited in a dose-dependent manner by 4e at concentrations orders of magnitude lower than toxic doses. Administration of 4e to D-galactosamine-sensitized mice challenged with supralethal doses of LPS provided significant protection against lethality. Potent antiendotoxic activity, low toxicity, and ease of synthesis render this class of compounds candidate endotoxin-sequestering agents of potential significant therapeutic value.

  DOI：

  10.1021/jm049449j

文献信息

• Polycationic sulfonamides and use thereof
  申请人：Burns Mark R.

  公开号：US20070287750A1

  公开（公告）日：2007-12-13

  Certain lipophilic polycationic sulfonamides are provided and are useful for treating various diseases or conditions and particularly sepsis.

  提供了某些亲脂性多阳离子磺胺类化合物，可用于治疗各种疾病或症状，尤其是败血症。
• Structure–activity relationships of lipopolysaccharide sequestration in N-alkylpolyamines
  作者：Anurupa Shrestha、Diptesh Sil、Subbalakshmi S. Malladi、Hemamali J. Warshakoon、Sunil A. David

  DOI：10.1016/j.bmcl.2009.03.055

  日期：2009.5

  We have previously shown that simple N-acyl or N-alkyl polyamines bind to and sequester Gram-negative bacterial lipopolysaccharide, affording protection against lethality in animal models of endotoxicosis. Several iterative design-and-test cycles of SAR studies, including high-throughput screens, had converged on compounds with polyamine scaffolds which have been investigated extensively with reference to the number, position, and length of acyl or alkyl appendages. However, the polyamine backbone itself had not been explored sufficiently, and it was not known if incremental variations on the polymethylene spacing would affect LPS-binding and neutralization properties. We have now systematically explored the relationship between variously elongated spermidine [NH2-(CH2)(3)-NH-(CH2)(4)-NH2] and norspermidine [NH2-(CH2)(3)-NH-(CH2)(3)-NH2] backbones, with the N-alkyl group being held constant at C-16 in order to examine if changing the spacing between the inner secondary amines may yield additional SAR information. We find that the norspermine-type compounds consistently showed higher activity compared to corresponding spermine homologues. (c) 2009 Elsevier Ltd. All rights reserved.
• US7411002B2
  申请人：——

  公开号：US7411002B2

  公开（公告）日：2008-08-12
• Lipopolysaccharide Sequestrants:  Structural Correlates of Activity and Toxicity in Novel Acylhomospermines
  作者：Kelly A. Miller、E. V. K. Suresh Kumar、Stewart J. Wood、Jens R. Cromer、Apurba Datta、Sunil A. David

  DOI：10.1021/jm049449j

  日期：2005.4.1

  Lipopolysaccharides (LPS), otherwise termed "endotoxins", are outer membrane constituents of Gram-negative bacteria. Lipopolysaccharides play a key role in the pathogenesis of "septic shock", a major cause of mortality in the critically ill patient. Therapeutic options aimed at limiting downstream systemic inflammatory processes by targeting lipopolysaccharide do not exist at the present time. We have defined the pharmacophore necessary for small molecules to specifically bind and neutralize LPS and, using animal models of sepsis, have shown that the sequestration of circulatory LPS by small molecules is a therapeutically viable strategy. In this paper, the interactions of a series of acylated homologated spermine compounds with LPS have been characterized. The optimal acyl chain length for effective sequestration of LPS was identified to be C-16 for the monoacyl compounds. The most promising of these compounds, 4e, binds LPS with an ED50 of 1.37 mu M. Nitric oxide production in murine J774A.1 cells, as well as TNF-alpha in human blood, is inhibited in a dose-dependent manner by 4e at concentrations orders of magnitude lower than toxic doses. Administration of 4e to D-galactosamine-sensitized mice challenged with supralethal doses of LPS provided significant protection against lethality. Potent antiendotoxic activity, low toxicity, and ease of synthesis render this class of compounds candidate endotoxin-sequestering agents of potential significant therapeutic value.
• Polycationic Sulfonamides for the Sequestration of Endotoxin
  作者：Mark R. Burns、Scott A. Jenkins、Matthew R. Kimbrell、Rajalakshmi Balakrishna、Thuan B. Nguyen、Benjamin G. Abbo、Sunil A. David

  DOI：10.1021/jm061198m

  日期：2007.2.1

  Lipopolysaccharides (LPS) play a key role in the pathogenesis of septic shock, a major cause of mortality in the critically ill patient. We had previously shown that monoacylated polyamine compounds specifically bind to and neutralize the activity of LPS with high in vitro potency and afford complete protection in a murine model of endotoxic shock. Fatty acid amides of polyamines may be rapidly cleared from systemic circulation due to their susceptibility to nonspecific serum amidases and, thus, would be predicted to have a short duration of action. In a systematic effort to increase the likelihood of better bioavailability properties together with structural modifications that may result in gains in activity, we now report structure-activity relationships pertaining to endotoxin-binding and -neutralizing activities of homologated polyamine sulfonamides.