13,15-Diamino-2-(aminomethyl)-3,4,9,12-tetrahydroxyhexadecahydro-2H-7,10-epoxypyrano[2,3-B][1,10,4]benzodioxazacyclododecin-8-YL 2,6-diamino-2,6-dideoxyhexopyranoside | 855520-57-9

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 13,15-Diamino-2-(aminomethyl)-3,4,9,12-tetrahydroxyhexadecahydro-2H-7,10-epoxypyrano[2,3-B][1,10,4]benzodioxazacyclododecin-8-YL 2,6-diamino-2,6-dideoxyhexopyranoside
• 英文别名: (1S,3R,4S,5R,7S,8R,10R,12R,13S,14R,15R,18R,19S,20R)-5,7-diamino-19-[(2R,3R,4R,5S,6S)-3-amino-6-(aminomethyl)-4,5-dihydroxyoxan-2-yl]oxy-12-(aminomethyl)-2,9,11,21-tetraoxa-16-azatetracyclo[16.2.1.03,8.010,15]henicosane-4,13,14,20-tetrol
• CAS: 855520-57-9
• 化学式: C₂₃H₄₄N₆O₁₂
• 分子量: 596.635
• InChiKey: DXIORKRGAWCDSD-LSWIJEOBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -8
• 重原子数：
  41
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  319
• 氢给体数：
  12
• 氢受体数：
  18

反应信息

• 作为反应物：
  描述：

  13,15-Diamino-2-(aminomethyl)-3,4,9,12-tetrahydroxyhexadecahydro-2H-7,10-epoxypyrano[2,3-B][1,10,4]benzodioxazacyclododecin-8-YL 2,6-diamino-2,6-dideoxyhexopyranoside 、 二碳酸二叔丁酯 在 三乙胺 作用下， 以 甲醇 为溶剂， 反应 16.0h， 以340 mg的产率得到
  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：

  在 水 作用下， 反应 120.0h， 以56%的产率得到13,15-Diamino-2-(aminomethyl)-3,4,9,12-tetrahydroxyhexadecahydro-2H-7,10-epoxypyrano[2,3-B][1,10,4]benzodioxazacyclododecin-8-YL 2,6-diamino-2,6-dideoxyhexopyranoside
  参考文献：
  名称：

  Exploring the Use of Conformationally Locked Aminoglycosides as a New Strategy to Overcome Bacterial Resistance

  摘要：

  The emergence of bacterial resistance to the major classes of antibiotics has become a serious problem over recent years. For aminoglycosides, the major biochemical mechanism for bacterial resistance is the enzymatic modification of the drug. Interestingly, in several cases, the oligosaccharide conformation recognized by the ribosomic RNA and the enzymes responsible for the antibiotic inactivation is remarkably different. This observation suggests a possible structure-based chemical strategy to overcome bacterial resistance; in principle, it should be possible to design a conformationally locked oligosaccharide that still retains antibiotic activity but that is not susceptible to enzymatic inactivation. To explore the scope and limitations of this strategy, we have synthesized several aminoglycoside derivatives locked in the ribosome-bound "bioactive" conformation. The effect of the structural preorganization on RNA binding, together with its influence on the aminoglycoside inactivation by several enzymes involved in bacterial resistance, has been studied. Our results indicate that the conformational constraint has a modest effect on their interaction with ribosomal RNA. In contrast, it may display a large impact on their enzymatic inactivation. Thus, the work presented herein provides a key example of how the conformational differences exhibited by these ligands within the binding pockets of the ribosome and of those enzymes involved in bacterial resistance can, in favorable cases, be exploited for designing new antibiotic derivatives with improved activity in resistant strains.

  DOI：

  10.1021/ja0543144

文献信息

• A Simple Structural-Based Approach to Prevent Aminoglycoside Inactivation by Bacterial Defense Proteins. Conformational Restriction Provides Effective Protection against Neomycin-B Nucleotidylation by ANT4
  作者：Juan Luis Asensio、Ana Hidalgo、Agatha Bastida、Mario Torrado、Francisco Corzana、Jose Luis Chiara、Eduardo García-Junceda、Javier Cañada、Jesús Jiménez-Barbero

  DOI：10.1021/ja051722z

  日期：2005.6.1

  Herein, we describe how the conformational differences exhibited by aminoglycosides in the binding pockets of the ribosome and those enzymes involved in bacterial resistance can be exploited in the design of new antibiotic derivatives with improved activity in resistant strains. The simple modification shown in the figure, leading to the conformationally restricted 5, provides an effective protection against aminoglycoside inactivation by Staphylococcus aureus ANT4, both in vivo and in vitro.