| 1356827-05-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• CAS: 1356827-05-8
• 化学式: C₂₂H₁₉Cl₃N₄O₆
• 分子量: 541.775
• InChiKey: FWXUQVHJGVHAEC-QWNWYNEWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.23
• 重原子数：
  35.0
• 可旋转键数：
  7.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  143.67
• 氢给体数：
  1.0
• 氢受体数：
  8.0

反应信息

• 作为反应物：
  描述：

  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

文献信息

• Exploring eukaryotic <i>versus</i> prokaryotic ribosomal RNA recognition with aminoglycoside derivatives
  作者：Narayana Murthy Sabbavarapu、Tomasz Pieńko、Bat-Hen Zalman、Joanna Trylska、Timor Baasov

  DOI：10.1039/c8md00001h

  日期：——

  ability to readthrough nonsense mutations was examined in vitro, along with the protein translation inhibition in prokaryotic and eukaryotic systems. The observed structure–activity relationships, along with the comparative molecular dynamics simulations within the eukaryotic rRNA decoding site, showed high sensitivity of 6′-position to substitution, indicating that the rational design of potent stop-codon

  设计、合成了在其环 I 上含有 6'-羧酸或 6'-酰胺的氨基糖苷类的新衍生物，并在体外检测了它们读取无义突变的能力，以及在原核和真核系统中的蛋白质翻译抑制。观察到的结构-活性关系，以及真核 rRNA 解码位点内的比较分子动力学模拟，显示出 6' 位对取代的高度敏感性，表明有效的终止密码子通读诱导剂的合理设计需要考虑不只有药物-RNA相互作用的结构和能量学，还有与这种相互作用相关的动力学。