7-(2'α-tert-butylvinylidene)cephalosporanic acid sulfone

• 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: 7-(2'α-tert-butylvinylidene)cephalosporanic acid sulfone
• 英文别名: (6R)-3-(acetyloxymethyl)-7-(3,3-dimethylbut-1-enylidene)-5,5,8-trioxo-5λ6-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
• 化学式: C₁₆H₁₉NO₇S
• 分子量: 369.395
• InChiKey: HFICAXNAWUOCGS-XJQCMFKWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.61
• 重原子数：
  25.0
• 可旋转键数：
  3.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  118.05
• 氢给体数：
  1.0
• 氢受体数：
  6.0

反应信息

• 作为产物：
  描述：

  7-氨基头孢烷酸 在 吡啶 、 盐酸 、 三氯化铝 、 三氟甲磺酸酐 、 pH=6.4 phosphate buffer 、 苯甲醚 、 三乙胺 、 间氯过氧苯甲酸 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 硝基苯 为溶剂， 反应 47.32h， 生成 7-(2'α-tert-butylvinylidene)cephalosporanic acid sulfone
  参考文献：
  名称：

  Synthesis and Mechanistic Evaluation of 7-Vinylidenecephem Sulfones as .beta.-Lactamase Inhibitors

  摘要：

  Representative 7-vinylidenecephalosporins 1 were synthesized from 7-aminocephalosporanic acid and were biologically evaluated as beta-lactamase inhibitors. These chiral allenes were prepared stereospecifically from a cephalosporin-derived propargylic triflate using organocopper reagents. The sodium salts of a few such unsaturated cephalosporanates were evaluated as beta-lactamase inhibitors of the type C enzyme derived from Enterobacter cloacae strain P99. One compound, sodium 7-(2'alpha-tert-butylvinylidene)cephalasporanate sulfone (16),was found to be an excellent progressive inhibitor of this enzyme, exhibiting a second-order rate constant of inactivation of k(3)' = 1.7 x 10(6) 1/(mol.min) and a turnover number of 12. A potential mechanism of inhibition was investigated. The corresponding terminally deuterated allene sodium 7-(2'alpha-tert-butyl-2'-beta-deuteriovinylidene) sulfone (21) was prepared and biologically evaluated. The deuterated compound inhibited the enzyme with a rate constant of k(3)' = 2.7 x 10(5) 1/(mol.min), representing an isotope effect of 6.3. The deuterated compound had an IC50 value which was approximately twice that of the protio compound, and had a turnover number of 25. A mechanism of inhibition which is consistent with this data was proposed. The mechanism of inhibition involves an acyl enzyme which becomes stabilized toward hydrolysis through its conversion-to a vinylogous urethane (beta-aminoacrylate). This intermediate is formed by an elimination reaction which transforms the allene into an enyne. The inhibition disappears extremely slowly, presumedly due to hydrolysis of the stabilized acyl enzyme. This pattern of reactivity is further confirmed by a H-1 NMR study of the nonenzymatic hydrolysis of the inhibitor under basic conditions. A second type of enzymatic inhibition, which does not disappear with time, was also observed. This second (irreversible) type of inhibition required longer incubation times and higher ratios of inhibitor to enzyme and showed no isotope effect.

  DOI：

  10.1021/ja00103a010

文献信息

• Synthesis and Mechanistic Evaluation of 7-Vinylidenecephem Sulfones as .beta.-Lactamase Inhibitors
  作者：John D. Buynak、Dipti Khasnis、Brian Bachmann、Kuangcong Wu、Grady Lamb

  DOI：10.1021/ja00103a010

  日期：1994.11

  Representative 7-vinylidenecephalosporins 1 were synthesized from 7-aminocephalosporanic acid and were biologically evaluated as beta-lactamase inhibitors. These chiral allenes were prepared stereospecifically from a cephalosporin-derived propargylic triflate using organocopper reagents. The sodium salts of a few such unsaturated cephalosporanates were evaluated as beta-lactamase inhibitors of the type C enzyme derived from Enterobacter cloacae strain P99. One compound, sodium 7-(2'alpha-tert-butylvinylidene)cephalasporanate sulfone (16),was found to be an excellent progressive inhibitor of this enzyme, exhibiting a second-order rate constant of inactivation of k(3)' = 1.7 x 10(6) 1/(mol.min) and a turnover number of 12. A potential mechanism of inhibition was investigated. The corresponding terminally deuterated allene sodium 7-(2'alpha-tert-butyl-2'-beta-deuteriovinylidene) sulfone (21) was prepared and biologically evaluated. The deuterated compound inhibited the enzyme with a rate constant of k(3)' = 2.7 x 10(5) 1/(mol.min), representing an isotope effect of 6.3. The deuterated compound had an IC50 value which was approximately twice that of the protio compound, and had a turnover number of 25. A mechanism of inhibition which is consistent with this data was proposed. The mechanism of inhibition involves an acyl enzyme which becomes stabilized toward hydrolysis through its conversion-to a vinylogous urethane (beta-aminoacrylate). This intermediate is formed by an elimination reaction which transforms the allene into an enyne. The inhibition disappears extremely slowly, presumedly due to hydrolysis of the stabilized acyl enzyme. This pattern of reactivity is further confirmed by a H-1 NMR study of the nonenzymatic hydrolysis of the inhibitor under basic conditions. A second type of enzymatic inhibition, which does not disappear with time, was also observed. This second (irreversible) type of inhibition required longer incubation times and higher ratios of inhibitor to enzyme and showed no isotope effect.