| 794524-05-3

• 分子结构分类: 有机化合物 - 有机氧化合物
• CAS: 794524-05-3
• 化学式: C₄₈H₈₅N₅O₂₄
• 分子量: 1116.22
• InChiKey: ZNNXXRDOKOYADJ-ACRBVWNSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.03
• 重原子数：
  77.0
• 可旋转键数：
  14.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.9
• 拓扑面积：
  408.87
• 氢给体数：
  13.0
• 氢受体数：
  24.0

反应信息

• 作为反应物：
  描述：

  在 吡啶 、 对甲苯磺酸 、 三乙胺 作用下， 以 甲醇 、 氯仿 、 N,N-二甲基甲酰胺 为溶剂， 反应 295.5h， 生成 C₄₃H₇₅N₅O₂₁
  参考文献：
  名称：

  Conformational Constraint as a Means for Understanding RNA-Aminoglycoside Specificity

  摘要：

  The lack of high RNA target selectivity displayed by aminoglycoside antibiotics results from both their electrostatically driven binding mode and their conformational adaptability. The inherent flexibility around their glycosidic bonds allows them to easily assume a variety of conformations, permitting them to structurally adapt to diverse RNA targets. This structural promiscuity results in the formation of aminoglycoside complexes with diverse RNA targets in which the antibiotics assume distinct conformations. Such differences suggest that covalently linking individual rings in an aminoglycoside could reduce its available conformations, thereby altering target selectivity. To explore this possibility, conformationally constrained neomycin and paromomycin analogues designed to mimic the A-site bound aminoglycoside structure have been synthesized and their affinities to the TAR and A-site, two therapeutically relevant RNA targets, have been evaluated. As per design, this constraint has minimal deleterious effect on binding to the A-site. Surprisingly, however, preorganizing these neomycin-class antibiotics into a TAR-disfavored structure has no deleterious effect on binding to this HIV-1 RNA sequence. We rationalize these observations by suggesting that the A-site and HIV TAR possess inherently different selectivities toward aminoglycosides. The inherent plasticity of the TAR RNA, coupled to the remaining flexibility within the conformationally constrained analogues, makes this RNA site an accommodating target for such polycationic ligands. In contrast, the deeply encapsulating A-site is a more discriminating RNA target, These observations suggest that future design of novel target selective RNA-based therapeutics will have to consider the inherent "structural" selectivity of the RNA target and not only the selectivity patterns displayed by the low molecular weight ligands.

  DOI：

  10.1021/ja050918w
• 作为产物：
  描述：

  二碳酸二叔丁酯 、 巴龙霉素 在 三乙胺 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 24.0h， 以58%的产率得到
  参考文献：
  名称：

  High-throughput Assay for Quantification of Aminoglycoside–Ribosome Interaction

  摘要：

  氨基糖苷类药物的严重副作用和耐氨基糖苷类药物菌株的扩散限制了氨基糖苷类药物的临床应用。与氨基糖苷类药物作用模式相同、分子骨架不同的化合物将成为氨基糖苷类药物的替代药物。在本研究中，我们构建了一个基于 SPR 的高通量筛选系统，用于发现此类化合物。

  DOI：

  10.1246/cl.160508

文献信息

• [EN] MEMBRANE-TARGETING AMINOGLYCOSIDE-BASED CATIONIC AMPHIPHILES AND THERAPEUTIC USES<br/>[FR] AMPHIPHILES CATIONIQUES À BASE D'AMINOGLYCOSIDE, CIBLANT LES MEMBRANES, ET UTILISATIONS THÉRAPEUTIQUES
  申请人：UNIV RAMOT

  公开号：WO2014013495A1

  公开（公告）日：2014-01-23

  The present invention relates to amphiphilic aminoglycoside (AG) derivatives, especially derivatives of tobramycin, kanamycin A and paromomycin comprising hydrophobic side chains linked to the AG moiety by various linkers. These novel derivatives are useful as broad spectrum antibacterial agents targeting bacterial cell membranes, while having minimal toxicity due to non-selective targeting of eukaryotic cell membranes. The present invention further relates to methods for preparing the novel derivatives, pharmaceutical compositions including such compounds, and methods of using these compounds and compositions, especially as membrane-targeting antibacterial agents for treating bacterial infections, and for inhibiting bio film growth.

  本发明涉及两性的氨基糖苷（AG）衍生物，特别是托布拉霉素、卡那霉素A和帕罗莫霉素的衍生物，这些衍生物包括通过各种连接剂连接到AG基团的疏水侧链。这些新颖的衍生物可用作靶向细菌细胞膜的广谱抗菌剂，同时由于对真核细胞膜的非选择性靶向作用，具有最小毒性。本发明还涉及制备这些新颖衍生物的方法、包括这些化合物的药物组合物、以及使用这些化合物和组合物的方法，特别是作为靶向细菌细胞膜的抗菌剂，用于治疗细菌感染和抑制生物膜生长。
• Di-alkylated paromomycin derivatives: Targeting the membranes of Gram positive pathogens that cause skin infections
  作者：Yifat Berkov-Zrihen、Ido M. Herzog、Mark Feldman、Adar Sonn-Segev、Yael Roichman、Micha Fridman

  DOI：10.1016/j.bmc.2013.03.046

  日期：2013.6

  A collection of paromomycin-based di-alkylated cationic amphiphiles differing in the lengths of their aliphatic chain residues were designed, synthesized, and evaluated against 14 Gram positive pathogens that are known to cause skin infections. Paromomycin derivatives that were di-alkylated with C-7 and C-8 linear aliphatic chains had improved antimicrobial activities relative to the parent aminoglycoside as well as to the clinically used membrane-targeting antibiotic gramicidin D; several novel derivatives were at least 16-fold more potent than the parent aminoglycoside paromomycin. Comparison between a di-alkylated and a mono-alkylated paromomycin indicated that the di-alkylation strategy leads to both an improvement in antimicrobial activity and to a dramatic reduction in undesired red blood cell hemolysis caused by many aminoglycoside-based cationic amphiphiles. Scanning electron microscopy provided evidence for cell surface damage by the reported di-alkylated paromomycins. (C) 2013 Elsevier Ltd. All rights reserved.