methyl (R)-2-((S)-3-hydroxybutyrylamino)-3-mercaptopropionate | 676346-96-6

• 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: methyl (R)-2-((S)-3-hydroxybutyrylamino)-3-mercaptopropionate
• CAS: 676346-96-6
• 化学式: C₈H₁₅NO₄S
• 分子量: 221.277
• InChiKey: SPKRKYAVTLKTNL-WDSKDSINSA-N

物化性质

• 熔点：
  84-86 °C(Solv: dichloromethane (75-09-2); hexane (110-54-3))
• 沸点：
  408.4±45.0 °C(Predicted)
• 密度：
  1.213±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.66
• 重原子数：
  14.0
• 可旋转键数：
  5.0
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  75.63
• 氢给体数：
  3.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  methyl (R)-2-((S)-3-hydroxybutyrylamino)-3-mercaptopropionate 在 palladium on activated charcoal N-溴代丁二酰亚胺(NBS) 、 氢气 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氯化碳 、 乙酸乙酯 、 甲苯 为溶剂， 生成 (8R,12R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-methoxy-1,12-dimethyl-10,14-dioxo-5,7,8,9,10,11,12,14-octahydro-13-oxa-6-thia-9-aza-benzocyclododecene-8-carboxylic acid methyl ester
  参考文献：
  名称：

  New Antibacterial Agents Derived from the DNA Gyrase Inhibitor Cyclothialidine

  摘要：

  Cyclothialidine (1, Ro 09-1437) is a potent DNA gyrase inhibitor that was isolated from Streptomyces filipinensis NR0484 and is a member of a new family of natural products. It acts by competitively inhibiting the ATPase activity exerted by the B subunit of DNA gyrase but barely exhibits any growth inhibitory activity against intact bacterial cells, presumably due to insufficient permeation of the cytoplasmic membrane. To explore the antibacterial potential of 1, we developed a flexible synthetic route allowing for the systematic modification of its structure. From a first set of analogues, structure-activity relationships (SAR) were established for different substitution patterns, and the 14-hydroxylated, bicyclic core (X) of 1 seemed to be the structural prerequisite for DNA gyrase inhibitory activity. The variation of the lactone ring size, however, revealed that activity can be found among 11- to 16-membered lactones, and even seco-analogues were shown to maintain some enzyme inhibitory properties, thereby reducing the minimal structural requirements to a rather simple, hydroxylated benzyl sulfide (XI). On the basis of these "minimal structures" a modification program afforded a number of inhibitors that showed in vitro activity against Gram-positive bacteria. The best activities were displayed by 14-membered lactones, and representatives of this subclass exhibit excellent and broad in vitro antibacterial activity against Gram-positive pathogens, including Staphylococcus aureus, Streptococcus pyogenes, and Enterococcus faecalis, and overcome resistance against clinically used drugs. By improving the pharmacokinetic properties of the most active compounds (94, 97), in particular by lowering their lipophilic properties, we were able to identify congeners of cyclothialidine (1) that showed efficacy in vivo.

  DOI：

  10.1021/jm0310232
• 作为产物：
  描述：

  (S)-3-羟基丁酸 、 L-半胱氨酸甲酯盐酸盐 在 N-甲基吗啉 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 作用下， 以 乙腈 为溶剂， 反应 3.0h， 以42%的产率得到methyl (R)-2-((S)-3-hydroxybutyrylamino)-3-mercaptopropionate
  参考文献：
  名称：

  New Antibacterial Agents Derived from the DNA Gyrase Inhibitor Cyclothialidine

  摘要：

  Cyclothialidine (1, Ro 09-1437) is a potent DNA gyrase inhibitor that was isolated from Streptomyces filipinensis NR0484 and is a member of a new family of natural products. It acts by competitively inhibiting the ATPase activity exerted by the B subunit of DNA gyrase but barely exhibits any growth inhibitory activity against intact bacterial cells, presumably due to insufficient permeation of the cytoplasmic membrane. To explore the antibacterial potential of 1, we developed a flexible synthetic route allowing for the systematic modification of its structure. From a first set of analogues, structure-activity relationships (SAR) were established for different substitution patterns, and the 14-hydroxylated, bicyclic core (X) of 1 seemed to be the structural prerequisite for DNA gyrase inhibitory activity. The variation of the lactone ring size, however, revealed that activity can be found among 11- to 16-membered lactones, and even seco-analogues were shown to maintain some enzyme inhibitory properties, thereby reducing the minimal structural requirements to a rather simple, hydroxylated benzyl sulfide (XI). On the basis of these "minimal structures" a modification program afforded a number of inhibitors that showed in vitro activity against Gram-positive bacteria. The best activities were displayed by 14-membered lactones, and representatives of this subclass exhibit excellent and broad in vitro antibacterial activity against Gram-positive pathogens, including Staphylococcus aureus, Streptococcus pyogenes, and Enterococcus faecalis, and overcome resistance against clinically used drugs. By improving the pharmacokinetic properties of the most active compounds (94, 97), in particular by lowering their lipophilic properties, we were able to identify congeners of cyclothialidine (1) that showed efficacy in vivo.

  DOI：

  10.1021/jm0310232