6'-N-AHB tobramycin

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 6'-N-AHB tobramycin
• 英文别名: (2S)-4-amino-N-[[(2R,3S,5R,6R)-5-amino-6-[(1R,2S,3S,4R,6S)-4,6-diamino-3-[(2S,3R,4S,5S,6R)-4-amino-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-3-hydroxyoxan-2-yl]methyl]-2-hydroxybutanamide
• 化学式: C₂₂H₄₄N₆O₁₁
• 分子量: 568.625
• InChiKey: KPKMHWJAHUKAJG-GKUFZQJASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -7.2
• 重原子数：
  39
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.95
• 拓扑面积：
  318
• 氢给体数：
  12
• 氢受体数：
  16

反应信息

• 作为产物：
  描述：

  硫酸妥布霉素 在 5% Pd(II)/C(eggshell) 、 氢气 、 potassium carbonate 作用下， 以 甲醇 、 水 、 乙腈 为溶剂， 反应 18.0h， 生成 6'-N-AHB tobramycin
  参考文献：
  名称：

  Assessment of 6′- and 6′′′-N-acylation of aminoglycosides as a strategy to overcome bacterial resistance

  摘要：

  为了恢复这类抗生素对耐药菌株的疗效，人们开发了许多合成氨基糖苷类似物，其中 1-N-acylated 类似物在临床上使用最多。在这项研究中，我们证明了临床常用化合物妥布霉素的 6â²-N-酰化和副黏菌素的 6â²â²-N-酰化可产生抗 6â²-氨基糖苷乙酰转移酶（AAC(6â²)）失活的衍生物。在对表达 AAC（6â²）或 AAC（3）的细菌以及致病细菌菌株进行测试时，与母体抗生素相比，一些类似物显示出更强的抗菌活性。研究发现，N-酰化类似物生物性能的提高与特定的氨基糖苷和酰基有很大关系。我们的研究表明，与 1-N-acylation 一样，氨基糖苷的 6â²- 和 6â²â²â²-N-acylation 也为寻找能够克服耐药菌感染的氨基糖苷类药物提供了另一个有前途的方向。

  DOI：

  10.1039/c0ob01133a

文献信息

• Synthesis and Biological Activity of Mono- and Di-<i>N</i>-acylated Aminoglycosides
  作者：Nishad Thamban Chandrika、Keith D. Green、Jacob L. Houghton、Sylvie Garneau-Tsodikova

  DOI：10.1021/acsmedchemlett.5b00255

  日期：2015.11.12

  Despite issues with oto/nephrotoxicity and bacterial resistance, aminoglycosides (AGs) remain an effective and widely used class of antibacterial agents. For decades now, efforts toward the development of novel AGs with potential to overcome some of these problems have been major research focuses. 1-N-Acylation, especially gamma-amino-beta-hydroxybutyrate (AHB) derivatization, has proven to be one of the most successful strategies for improving the overall properties of AGs, including their ability to avoid certain resistance mechanisms. More recently, 6'-N-acylation arose as another possible strategy to improve the properties of these drugs. In this study, we report on the glycinyl, carboxybenzyl, and AHB mono- and diderivatization at the 1-, 6'-, and/or 4'''-amines of the AGs amikacin, kanamycin A, netilmicin, sisomicin, and tobramycin. We also present the antibacterial activities and the reduced reactivity of AG-modifying enzymes (AMEs) toward these new AG derivatives, and identify the AMEs present in the bacterial strains tested.
• Assessment of 6′- and 6′′′-N-acylation of aminoglycosides as a strategy to overcome bacterial resistance
  作者：Pazit Shaul、Keith D. Green、Roi Rutenberg、Maria Kramer、Yifat Berkov-Zrihen、Elinor Breiner-Goldstein、Sylvie Garneau-Tsodikova、Micha Fridman

  DOI：10.1039/c0ob01133a

  日期：——

  Amongst the many synthetic aminoglycoside analogues that were developed to regain the efficacy of this class of antibiotics against resistant bacterial strains, the 1-N-acylated analogues are the most clinically used. In this study we demonstrate that 6′-N-acylation of the clinically used compound tobramycin and 6′′′-N-acylation of paromomycin result in derivatives resistant to deactivation by 6′-aminoglycoside acetyltransferase (AAC(6′)) which is widely found in aminoglycoside resistant bacteria. When tested against AAC(6′)- or AAC(3)-expressing bacteria as well as pathogenic bacterial strains, some of the analogues demonstrated improved antibacterial activity compared to their parent antibiotics. Improvement of the biological performance of the N-acylated analogues was found to be highly dependent on the specific aminoglycoside and acyl group. Our study indicates that as for 1-N-acylation, 6′- and 6′′′-N-acylation of aminoglycosides offer an additional promising direction in the search for aminoglycosides capable of overcoming infections by resistant bacteria.

  为了恢复这类抗生素对耐药菌株的疗效，人们开发了许多合成氨基糖苷类似物，其中 1-N-acylated 类似物在临床上使用最多。在这项研究中，我们证明了临床常用化合物妥布霉素的 6â²-N-酰化和副黏菌素的 6â²â²-N-酰化可产生抗 6â²-氨基糖苷乙酰转移酶（AAC(6â²)）失活的衍生物。在对表达 AAC（6â²）或 AAC（3）的细菌以及致病细菌菌株进行测试时，与母体抗生素相比，一些类似物显示出更强的抗菌活性。研究发现，N-酰化类似物生物性能的提高与特定的氨基糖苷和酰基有很大关系。我们的研究表明，与 1-N-acylation 一样，氨基糖苷的 6â²- 和 6â²â²â²-N-acylation 也为寻找能够克服耐药菌感染的氨基糖苷类药物提供了另一个有前途的方向。