3',4',6',6-tetra-O-acetyl-2',3-diazido-1-N-[(S)-4-azido-2-O-acetyl-butanoyl]-6'-(R)-methyl-paromamine | 1375073-77-0

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 3',4',6',6-tetra-O-acetyl-2',3-diazido-1-N-[(S)-4-azido-2-O-acetyl-butanoyl]-6'-(R)-methyl-paromamine
• CAS: 1375073-77-0
• 化学式: C₂₇H₃₈N₁₀O₁₄
• 分子量: 726.657
• InChiKey: GAQVIYFLEXQKPW-BZNDFYELSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.08
• 重原子数：
  51.0
• 可旋转键数：
  15.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.78
• 拓扑面积：
  345.57
• 氢给体数：
  2.0
• 氢受体数：
  17.0

反应信息

• 作为反应物：
  描述：

  3',4',6',6-tetra-O-acetyl-2',3-diazido-1-N-[(S)-4-azido-2-O-acetyl-butanoyl]-6'-(R)-methyl-paromamine 在 甲胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 10.34h， 生成 ELX-05
  参考文献：
  名称：

  Increased Selectivity toward Cytoplasmic versus Mitochondrial Ribosome Confers Improved Efficiency of Synthetic Aminoglycosides in Fixing Damaged Genes: A Strategy for Treatment of Genetic Diseases Caused by Nonsense Mutations

  摘要：

  Compelling evidence is now available that gentamicin and Geneticin (G418) can induce the mammalian ribosome to suppress disease-causing nonsense mutations and partially restore the expression of functional proteins. However, toxicity and relative lack of efficacy at subtoxic doses limit the use of gentamicin for suppression therapy. Although G418 exhibits the strongest activity, it is very cytotoxic even at low doses. We describe here the first systematic development of the novel aminoglycoside (S)-11 exhibiting similar in vitro and ex vivo activity to that of G418, while its cell toxicity is significantly lower than those of gentamicin and G418. Using a series of biochemical assays, we provide proof of principle that antibacterial activity and toxicity of aminoglycosides can be dissected from their suppression activity. The data further indicate that the increased specificity toward cytoplasmic ribosome correlates with the increased activity and that the decreased specificity toward mitochondrial ribosome confers the lowered cytotoxicity.

  DOI：

  10.1021/jm3012992
• 作为产物：
  描述：

  2',3-diazido-1-N-[(S)-4-azido-2-hydroxybutanoyl]-6'-(R)-methyl-paromamine 、 乙酸酐 在 吡啶 作用下， 反应 16.0h， 以70%的产率得到3',4',6',6-tetra-O-acetyl-2',3-diazido-1-N-[(S)-4-azido-2-O-acetyl-butanoyl]-6'-(R)-methyl-paromamine
  参考文献：
  名称：

  Repairing faulty genes by aminoglycosides: Development of new derivatives of geneticin (G418) with enhanced suppression of diseases-causing nonsense mutations

  摘要：

  New pseudo-di- and pseudo-trisaccharide derivatives of the aminoglycoside drug G418 were designed, synthesized and their ability to readthrough nonsense mutations was examined in both in vitro and ex vivo systems, along with the toxicity tests. Two novel lead structures, NB74 and NB84, exhibiting significantly reduced cell toxicity and superior readthrough efficiency than those of gentamicin, were discovered. The superiority of new leads was demonstrated in six different nonsense DNA-constructs underling the genetic diseases cystic fibrosis, Duchenne muscular dystrophy, Usher syndrome and Hurler syndrome. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2010.03.060

文献信息

• [EN] AMINOGLYCOSIDES AND USES THEREOF IN TREATING GENETIC DISORDERS<br/>[FR] AMINOGLYCOSIDES ET LEURS UTILISATIONS DANS LE TRAITEMENT DES TROUBLES GÉNÉTIQUES
  申请人：TECHNION RES & DEV FOUNDATION

  公开号：WO2012066546A1

  公开（公告）日：2012-05-24

  A new class of pseudo-trisaccharide aminoglycosides having an alkyl group at the 5'' position, exhibiting efficient stop codon mutation readthrough activity, low cytotoxicity and high selectivity towards eukaryotic translation systems are provided. Also provided are pharmaceutical compositions containing the same, and uses thereof in the treatment of genetic disorders, as well as processes of preparing these aminoglycosides. The disclosed aminoglycosides can be represented by the general formula I: formula I or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of alkyl, cycloalkyl and aryl; and all other variables and features are as described in the specification.

  提供了一类新型的伪三糖氨基糖苷类化合物，其在5''位具有烷基基团，表现出高效的终止密码子突变读穿活性，低细胞毒性和高选择性作用于真核翻译系统。还提供了含有这些化合物的药物组合物，以及在治疗遗传疾病中的用途，以及制备这些氨基糖苷类化合物的方法。所披露的氨基糖苷类化合物可以用通用公式I表示：公式I或其药用可接受的盐，其中R1选自烷基、环烷基和芳基组成的群体；以及所有其他变量和特征如规范中所述。