N-(9-fluorenylmethoxycarbonyl)glycyl-3-aminopropanal | 911368-25-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 芴
• 英文名称: N-(9-fluorenylmethoxycarbonyl)glycyl-3-aminopropanal
• 英文别名: 9H-fluoren-9-ylmethyl N-[2-oxo-2-(3-oxopropylamino)ethyl]carbamate
• CAS: 911368-25-7
• 化学式: C₂₀H₂₀N₂O₄
• 分子量: 352.39
• InChiKey: JFYVAHPCYKPGFT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  26
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  84.5
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-(9-fluorenylmethoxycarbonyl)glycyl-3-aminopropanal 在 哌啶 、 sodium cyanoborohydride 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 生成
  参考文献：
  名称：

  Large Molecular Assembly of Amphotericin B Formed in Ergosterol-Containing Membrane Evidenced by Solid-State NMR of Intramolecular Bridged Derivative

  摘要：

  Amphotericin B (AmB 1) is known to assemble and form an ion channel across biomembranes. We have recently reported that conformation-restricted derivatives of AmB 2-4 show different ergosterol preferences in ion-channel assays, which suggested that the orientation of the mycosamine strongly affects the sterol selectivity of AmB. The data allowed us to assume that compound 3 showing the highest selectivity would reflect the active conformation of AmB in the channel assembly. In this study, to gain further insight into the active conformation of AmB, we prepared a new intramolecular-bridged derivative 5, where the linker encompassed a hydrophilic glycine moiety. The derivative has almost equivalent ion-channel activity to those of AmB and 3. The antifungal activity of 5 compared with 3 improves significantly, possibly because the increasing hydrophilicity in the linker enhances the penetrability through the fungal cell wall. Conformation of 5 was well converged and very similar to that of 3, thus further supporting the notion that the conformations of these derivatives reproduce the active structure of AmB in the channel complex. Then we used the derivative to probe the mobility of AmB in the membrane by solid-state NMR. To measure dipolar couplings and chemical shift anisotropies, we incorporated [1-C-13, N-15] glycine into the linker. The results indicate that 5 is mostly immobilized in ergosterol-containing DMPC bilayers, implying formation of large aggregates of 5. Meanwhile some fraction of 5 remains mobile in sterol-free DMPC bilayers, suggesting promotion of AmB aggregation by ergosterol.

  DOI：

  10.1021/ja063433w
• 作为产物：
  描述：

  (9H-fluoren-9-yl)methyl {(3-hydroxypropylcarbamoyl)methyl}carbamate 在 戴斯-马丁氧化剂 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 以72%的产率得到N-(9-fluorenylmethoxycarbonyl)glycyl-3-aminopropanal
  参考文献：
  名称：

  Large Molecular Assembly of Amphotericin B Formed in Ergosterol-Containing Membrane Evidenced by Solid-State NMR of Intramolecular Bridged Derivative

  摘要：

  Amphotericin B (AmB 1) is known to assemble and form an ion channel across biomembranes. We have recently reported that conformation-restricted derivatives of AmB 2-4 show different ergosterol preferences in ion-channel assays, which suggested that the orientation of the mycosamine strongly affects the sterol selectivity of AmB. The data allowed us to assume that compound 3 showing the highest selectivity would reflect the active conformation of AmB in the channel assembly. In this study, to gain further insight into the active conformation of AmB, we prepared a new intramolecular-bridged derivative 5, where the linker encompassed a hydrophilic glycine moiety. The derivative has almost equivalent ion-channel activity to those of AmB and 3. The antifungal activity of 5 compared with 3 improves significantly, possibly because the increasing hydrophilicity in the linker enhances the penetrability through the fungal cell wall. Conformation of 5 was well converged and very similar to that of 3, thus further supporting the notion that the conformations of these derivatives reproduce the active structure of AmB in the channel complex. Then we used the derivative to probe the mobility of AmB in the membrane by solid-state NMR. To measure dipolar couplings and chemical shift anisotropies, we incorporated [1-C-13, N-15] glycine into the linker. The results indicate that 5 is mostly immobilized in ergosterol-containing DMPC bilayers, implying formation of large aggregates of 5. Meanwhile some fraction of 5 remains mobile in sterol-free DMPC bilayers, suggesting promotion of AmB aggregation by ergosterol.

  DOI：

  10.1021/ja063433w

文献信息

• Amphotericin B covalent dimers with carbonyl-amino linkage: a new probe for investigating ion channel assemblies
  作者：Yuichi Umegawa、Nobuaki Matsumori、Tohru Oishi、Michio Murata

  DOI：10.1016/j.tetlet.2007.03.058

  日期：2007.5

  Based on an amphotericin B (AmB) ion-channel model where the close proximity of neighboring molecules is effected by interaction between carboxyl and amino groups, we prepared covalent dimers of AmB connected between these functionalities. While directly connected and short-tethered derivatives (2 and 3) lacked the activities, dimer 4 with a longer linker revealed K+ ion flux activity, suggesting that some distance and/or flexibility between the carboxyl and amino groups in adjacent molecules is required for the formation of ion-permeable complex in biomembranes. (c) 2007 Elsevier Ltd. All rights reserved.
• Possible conformation of amphotericin B dimer in membrane-bound assembly as deduced from solid-state NMR
  作者：Yuichi Umegawa、Takeshi Adachi、Nobuaki Matsumori、Michio Murata

  DOI：10.1016/j.bmc.2012.08.016

  日期：2012.10

  Aiming for structural analysis of amphotericin B (AmB) ion-channel assemblies in membrane, a covalent dimer was synthesized between C-13-labled AmB methyl ester and F-19-labled AmB. The dimer showed slightly weaker but significant biological activities against fungi and red blood cells compared with those of monomeric AmB. Then the dimer was subjected to C-13F-19}REDOR (Rotational-Echo Double Resonance) experiments in hydrated lipid bilayers. The obtained REDOR dephasing effects were explained by two components; a short C-13/F-19 distance (6.9 angstrom) accounting for 23% of the REDOR dephasing, and a longer one (14 angstrom) comprising the rest of the dephasing. The shorter distance is likely to reflect the formation of barrel-stave ion channel. (C) 2012 Elsevier Ltd. All rights reserved.
• [EN] PROCESS FOR THE PREPARATION OF PEGYLATED DRUG-LINKERS AND INTERMEDIATES THEREOF<br/>[FR] PROCÉDÉ DE PRÉPARATION DE LIEURS DE MÉDICAMENTS PÉGYLÉS ET LEURS INTERMÉDIAIRES
  申请人：SEATTLE GENETICS INC

  公开号：WO2017165851A1

  公开（公告）日：2017-09-28

  The present invention provides improved processes for the preparation of auristatin drug-linkers with a PEG unit, as well as intermediates thereof.