vancomycin 3-N,N-dimethylaminopropanamide

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: vancomycin 3-N,N-dimethylaminopropanamide
• 英文别名: (1S,2R,18R,19R,22S,25R,28R,40S)-48-[(2S,3R,4S,5S,6R)-3-[(2S,4S,5S,6S)-4-amino-5-hydroxy-4,6-dimethyloxan-2-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-22-(2-amino-2-oxoethyl)-5,15-dichloro-N-[3-(dimethylamino)propyl]-2,18,32,35,37-pentahydroxy-19-[[(2R)-4-methyl-2-(methylamino)pentanoyl]amino]-20,23,26,42,44-pentaoxo-7,13-dioxa-21,24,27,41,43-pentazaoctacyclo[26.14.2.23,6.214,17.18,12.129,33.010,25.034,39]pentaconta-3,5,8(48),9,11,14,16,29(45),30,32,34(39),35,37,46,49-pentadecaene-40-carboxamide
• 化学式: C₇₁H₈₇Cl₂N₁₁O₂₃
• 分子量: 1533.44
• InChiKey: ACNJDAQLGXKYCI-IPINHLIKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.2
• 重原子数：
  107
• 可旋转键数：
  17
• 环数：
  12.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  526
• 氢给体数：
  19
• 氢受体数：
  26

反应信息

• 作为产物：
  描述：

  万古霉素 、 N,N-二甲基-1,3-二氨基丙烷 在 N-甲基吗啉 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 作用下， 以 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 以64%的产率得到vancomycin 3-N,N-dimethylaminopropanamide
  参考文献：
  名称：

  [Ψ[CH2NH] Tpg4]万古霉素的外围修饰及协同作用机制，提供了持久而有效的抗生素

  摘要：

  设计用于提供双d -Ala- d -Ala / d -Ala- d -Lac结合的结合口袋修饰后，该结合口袋修饰直接克服了万古霉素耐药性的分子基础，因此已探索了外围结构变化以提高抗菌效力并提供其他协同机制行动。C-末端周边改性，引入季铵盐，被报告，并且发现，以提供一个结合口袋改性万古霉素类似物与动作的第二机构，其独立的d -Ala- d -Ala / d -Ala- d-Lac绑定。发现这种修饰可诱导细胞壁通透性，并与糖肽抑制细胞壁合成相辅相成，可改善对万古霉素耐药肠球菌（VRE）的抗菌效力（200倍）。此外，已表明这种C末端修饰可以与万古霉素二糖中的第二种外围（4-氯联苯）甲基（CBP）结合使用，以提供更有效的抗菌剂[VRE最小抑菌浓度（MIC）= 0.01–0.005μg/ mL]的活性可归因于三种独立的协同作用机制，其中只有一种需要d -Ala- d -Ala / d -Ala- d

  DOI：

  10.1073/pnas.1704125114

文献信息

• [EN] PERIPHERAL MODIFICATIONS ON POCKET-REDESIGNED VANCOMYCIN ANALOGS SYNERGISTICALLY IMPROVE ANTIMICROBIAL POTENCY AND DURABILITY<br/>[FR] MODIFICATIONS PÉRIPHÉRIQUES SUR DES ANALOGUES DE VANCOMYCINE À POCHE RECONÇUES POUR AMÉLIORER DE MANIÈRE SYNERGIQUE LA PUISSANCE ANTIMICROBIENNE ET LA DURABILITÉ
  申请人：SCRIPPS RESEARCH INST

  公开号：WO2018081797A1

  公开（公告）日：2018-05-03

  A C-terminus modification to a binding pocket-modified vancomycin introduces a quaternary ammonium salt that provides a binding pocket-modified vancomycin analog with a second mechanism of action that is independent of D-Ala-D-Ala/D-Ala-D-Lac binding. The modification disrupts cell wall integrity and induces cell wall permeability complementary to the glycopeptide inhibition of cell wall synthesis, and provides synergistic improvements in antimicrobial potency (200-fold) against vancomycin-resistant bacteria. Combining the C- terminus and binding pocket modifications with an orthogonal (4-chlorobiphenyl ) methyl addition to the vancomycin disaccharide provides even more potent antimicrobial agents whose activity can be attributed to three independent and synergistic mechanisms of action, only one of which requires D-Ala-D-Ala/D-Ala- D-Lac binding. The resulting modified vancomycins display little propensity for acquired resistance through serial exposure of vancomycin-resistant Enterococci and their durability against such challenges as well as their antimicrobial potency follow predicable trends. Methods of treatment with and compositions containing the modified vancomycins are disclosed.

  一种对结合口袋改性的万古霉素进行C-末端修饰，引入了一个季铵盐，为结合口袋改性的万古霉素类似物引入了第二个作用机制，与D-Ala-D-Ala/D-Ala-D-Lac结合无关。这种修饰破坏了细胞壁完整性，诱导了细胞壁通透性，与糖肽抑制细胞壁合成相辅相成，并提供了与万古霉素耐药细菌的协同改进（提高200倍）的抗微生物活性。将C-末端和结合口袋改性与万古霉素二糖的一个正交（4-氯联苯）甲基添加相结合，提供了更强效的抗微生物剂，其活性可归因于三种独立且协同作用的机制，其中只有一种需要D-Ala-D-Ala/D-Ala-D-Lac结合。结果修饰后的万古霉素类药物在连续暴露于万古霉素耐药肠球菌后，几乎没有获得性耐药性的倾向，它们对抗这种挑战的耐久性以及抗微生物活性遵循可预测的趋势。公开了使用和含有修饰后的万古霉素的治疗方法和组合物。
• Multivalent Drug Design. Synthesis and In Vitro Analysis of an Array of Vancomycin Dimers
  作者：John H. Griffin、Martin S. Linsell、Matthew B. Nodwell、QiQi Chen、John L. Pace、Kelly L. Quast、Kevin M. Krause、Lesley Farrington、Terry X. Wu、Deborah L. Higgins、Thomas E. Jenkins、Burton G. Christensen、J. Kevin Judice

  DOI：10.1021/ja021273s

  日期：2003.5.1

  The design, synthesis, and in vitro microbiological analysis of an array of forty covalently linked vancomycin dinners are reported. This work was undertaken to systematically probe the impact of linkage orientation and linker length on biological activity against susceptible and drug-resistant Gram-positive pathogens. To prepare the array, monomeric vancomycin synthons were linked through four distinct positions of the glycopeptide (C-terminus (C), N-terminus (N), vancosamine residue (V), and resorcinol ring (R)) in 10 unique pairwise combinations. Amphiphilic, peptide-based linkers of four different lengths (111, 19, 27, and 43 total atoms) were employed. Both linkage orientation and linker length were found to affect in vitro antibacterial potency. The V-V series displayed the greatest potency against vancomycin-susceptible organisms and vancomycin-resistant Enterococcus faecalis (VRE) of VanB phenotype, while the C-C, C-V, and V-R series displayed the most promising broad-spectrum activity that included VRE of VanA phenotype. Dimers bearing the shortest linkers were in all cases preferred for activity against VRE. The effects of linkage orientation and linker length on in vitro potency were not uniform; for example, (1) no single compound displayed activity that was superior against all test organisms to that of vancomycin or the other dimers, (2) linker length effects varied with test organism, and (3) whereas one-half of the dimers were more potent than vancomycin against methicillin-susceptible Staphylococcus aureus (MSSA), only one dimer was more potent against methicillin-resistant S. aureus (MRSA) and glycopeptide-intermediate susceptible S. aureus (GISA). In interpreting the results, we have considered the potential roles of multivalency and of other phenomena.