tert-butyl N-[N'-[4-[[26,27-bis[4-[bis[(2-methylpropan-2-yl)oxycarbonylamino]methylideneamino]butoxy]-5,11,17,23-tetratert-butyl-28-[4-[(2-methylpropan-2-yl)oxycarbonylamino]butoxy]-25-pentacyclo[19.3.1.13,7.19,13.115,19]octacosa-1(25),3,5,7(28),9(27),10,12,15(26),16,18,21,23-dodecaenyl]oxy]butyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamimidoyl]carbamate

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: tert-butyl N-[N'-[4-[[26,27-bis[4-[bis[(2-methylpropan-2-yl)oxycarbonylamino]methylideneamino]butoxy]-5,11,17,23-tetratert-butyl-28-[4-[(2-methylpropan-2-yl)oxycarbonylamino]butoxy]-25-pentacyclo[19.3.1.13,7.19,13.115,19]octacosa-1(25),3,5,7(28),9(27),10,12,15(26),16,18,21,23-dodecaenyl]oxy]butyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamimidoyl]carbamate
• 化学式: C₉₈H₁₅₄N₁₀O₁₈
• 分子量: 1760.36
• InChiKey: BISLBJODBNJNAU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  25.9
• 重原子数：
  126
• 可旋转键数：
  48
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  342
• 氢给体数：
  7
• 氢受体数：
  21

反应信息

• 作为反应物：
  描述：

  tert-butyl N-[N'-[4-[[26,27-bis[4-[bis[(2-methylpropan-2-yl)oxycarbonylamino]methylideneamino]butoxy]-5,11,17,23-tetratert-butyl-28-[4-[(2-methylpropan-2-yl)oxycarbonylamino]butoxy]-25-pentacyclo[19.3.1.13,7.19,13.115,19]octacosa-1(25),3,5,7(28),9(27),10,12,15(26),16,18,21,23-dodecaenyl]oxy]butyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamimidoyl]carbamate 、 三氟乙酸 在 苯甲醚 作用下， 以 二氯甲烷 为溶剂， 以82%的产率得到5,11,17,23-tetra-tert-butyl-25,26,27-tris(4-guanidinobutyroxy)-28-(4-aminobutyroxy) calix[4]arene heptatrifluoroacetic acid salt
  参考文献：
  名称：

  Topomimetics of Amphipathic β-Sheet and Helix-Forming Bactericidal Peptides Neutralize Lipopolysaccharide Endotoxins

  摘要：

  Release of lipopolysaccharide (LPS) endotoxin from Gram negative bacterial membranes triggers macrophages to produce large quantities of cytokines that can lead to septic shock and eventual death. Agents that bind to and neutralize LPS may provide a means to clinically prevent septic shock upon bacterial infection. Previously, we reported the design of antibacterial helix peptide SC4 and beta-sheet-forming beta pep peptides that neutralize LPS in vitro. We hypothesized that the ability of these and other such peptides to neutralize LPS rested in the common denominator of positively charged amphipathic structure. Here, we describe the design and synthesis of nonpeptide, calixarene-based helix/sheet topomimetics that mimic the folded conformations of these peptides in their molecular dimensions, amphipathic surface topology, and compositional properties. From a small library of topomimetics, we identified several compounds that neutralize LPS in the 10(-8) M range, making them as effective as bactericidal/permeability increasing protein and polymyxin B. In an endotoxemia mouse model, three of the most in vitro effective topomimetics are shown to be at least partially protective against challenges of LPS from different bacterial species. NMR studies provide mechanistic insight by suggesting the site of molecular interaction between topomimetics and the lipid A component of LPS, with binding being mediated by electrostatic and hydrophobic interactions. This research contributes to the development of pharmaceutical agents against endotoxemia and septic shock.

  DOI：

  10.1021/jm0610447
• 作为产物：
  描述：

  N,N'-bis-Boc-S-methyl-isothiourea 、 5,11,17,23-Tetra-p-tert-butyl-25,26,27,28-tetrakis<(aminobutyl)oxy>calix<4>arene 在 三乙胺 、 mercury dichloride 作用下， 以 二氯甲烷 为溶剂， 反应 15.0h， 以36%的产率得到5,11,17,23-Tetra-tert-butyl-25,26,27,28-tetrakis[4-(bis-Boc-guanidine)butoxy]calix[4]arene
  参考文献：
  名称：

  Topomimetics of Amphipathic β-Sheet and Helix-Forming Bactericidal Peptides Neutralize Lipopolysaccharide Endotoxins

  摘要：

  Release of lipopolysaccharide (LPS) endotoxin from Gram negative bacterial membranes triggers macrophages to produce large quantities of cytokines that can lead to septic shock and eventual death. Agents that bind to and neutralize LPS may provide a means to clinically prevent septic shock upon bacterial infection. Previously, we reported the design of antibacterial helix peptide SC4 and beta-sheet-forming beta pep peptides that neutralize LPS in vitro. We hypothesized that the ability of these and other such peptides to neutralize LPS rested in the common denominator of positively charged amphipathic structure. Here, we describe the design and synthesis of nonpeptide, calixarene-based helix/sheet topomimetics that mimic the folded conformations of these peptides in their molecular dimensions, amphipathic surface topology, and compositional properties. From a small library of topomimetics, we identified several compounds that neutralize LPS in the 10(-8) M range, making them as effective as bactericidal/permeability increasing protein and polymyxin B. In an endotoxemia mouse model, three of the most in vitro effective topomimetics are shown to be at least partially protective against challenges of LPS from different bacterial species. NMR studies provide mechanistic insight by suggesting the site of molecular interaction between topomimetics and the lipid A component of LPS, with binding being mediated by electrostatic and hydrophobic interactions. This research contributes to the development of pharmaceutical agents against endotoxemia and septic shock.

  DOI：

  10.1021/jm0610447

文献信息

• [EN] CALIXARENE-BASED PEPTIDE CONFORMATION MIMETICS, METHODS OF USE, AND METHODS OF MAKING<br/>[FR] MIMETIQUES A CONFORMATION PEPTIDIQUE A BASE DE CALIXARENE, PROCEDES D'UTILISATION, ET PROCEDES D'ELABORATION
  申请人：UNIV MINNESOTA

  公开号：WO2006042104A3

  公开（公告）日：2007-01-18
• Topomimetics of Amphipathic β-Sheet and Helix-Forming Bactericidal Peptides Neutralize Lipopolysaccharide Endotoxins
  作者：Xuemei Chen、Ruud P. M. Dings、Irina Nesmelova、Stefan Debbert、Judith R. Haseman、Jacques Maxwell、Thomas R. Hoye、Kevin H. Mayo

  DOI：10.1021/jm0610447

  日期：2006.12.1

  Release of lipopolysaccharide (LPS) endotoxin from Gram negative bacterial membranes triggers macrophages to produce large quantities of cytokines that can lead to septic shock and eventual death. Agents that bind to and neutralize LPS may provide a means to clinically prevent septic shock upon bacterial infection. Previously, we reported the design of antibacterial helix peptide SC4 and beta-sheet-forming beta pep peptides that neutralize LPS in vitro. We hypothesized that the ability of these and other such peptides to neutralize LPS rested in the common denominator of positively charged amphipathic structure. Here, we describe the design and synthesis of nonpeptide, calixarene-based helix/sheet topomimetics that mimic the folded conformations of these peptides in their molecular dimensions, amphipathic surface topology, and compositional properties. From a small library of topomimetics, we identified several compounds that neutralize LPS in the 10(-8) M range, making them as effective as bactericidal/permeability increasing protein and polymyxin B. In an endotoxemia mouse model, three of the most in vitro effective topomimetics are shown to be at least partially protective against challenges of LPS from different bacterial species. NMR studies provide mechanistic insight by suggesting the site of molecular interaction between topomimetics and the lipid A component of LPS, with binding being mediated by electrostatic and hydrophobic interactions. This research contributes to the development of pharmaceutical agents against endotoxemia and septic shock.