p-nitrobenzyl 6α-bromo-6β-(hydroxymethyl)penicillanate | 171671-47-9

• 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: p-nitrobenzyl 6α-bromo-6β-(hydroxymethyl)penicillanate
• 英文别名: (4-nitrophenyl)methyl (2S,5R,6S)-6-bromo-6-(hydroxymethyl)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate
• CAS: 171671-47-9
• 化学式: C₁₆H₁₇BrN₂O₆S
• 分子量: 445.291
• InChiKey: WXFXWCSPOOUGSY-PEYYIBSZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  26
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  138
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  p-nitrobenzyl 6α-bromo-6β-(hydroxymethyl)penicillanate 在 palladium on activated charcoal 三丁基膦 、 sodium phosphate buffer 、 氢气 作用下， 以 甲醇 、 水 为溶剂， 反应 1.5h， 生成 6α-(hydroxymethyl)penicillanic acid
  参考文献：
  名称：

  Design, Synthesis, and Evaluation of a Potent Mechanism-Based Inhibitor for the TEM .beta.-Lactamase with Implications for the Enzyme Mechanism

  摘要：

  The design, synthesis, and evaluation of 6 alpha-(hydroxymethyl)penicillanic acid (4) as a new mechanism-based inhibitor for the class A TEM-1 beta-lactamase is described. The design of this compound was aided by computer modeling, using the high-resolution crystal structure for the TEM-1 beta-lactamase. The molecule is believed to displace the hydrolytic water molecule (Wat-712) with its hydroxymethyl function. This interaction would impart longevity to the acyl-enzyme intermediate, accounting for the onset of inhibition, a process that results in an 11-h period for recovery of 90% of activity for the inhibited enzymes. This molecule inhibited the TEM-1 beta-lactamase rapidly, for which the kinetic parameters were evaluate. The molecule showed a partition ratio (i.e., k(cat)/k(inact)) of 28+/-2, a value which is lower than the corresponding parameter for all of the clinically used class A beta-lactamase inactivators. The design concepts outlined for 6 alpha-(hydroxymethyl)penicillanic acid as an inhibitor support the mechanistic roles proposed for Glu-166 and Wat-712 in the deacylation step for turnover chemistry by class A beta-lactamases. Furthermore, the principles that we disclose herein for the design of compound 4 as an inhibitor for beta-lactamases should be of general interest for designing specific inhibitors for any hydrolytic enzyme for which high-resolution crystal structure is available.

  DOI：

  10.1021/ja00150a003
• 作为产物：
  描述：

  对硝基溴化苄 在 甲基溴化镁 、 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.5h， 生成 p-nitrobenzyl 6α-bromo-6β-(hydroxymethyl)penicillanate
  参考文献：
  名称：

  Design, Synthesis, and Evaluation of a Potent Mechanism-Based Inhibitor for the TEM .beta.-Lactamase with Implications for the Enzyme Mechanism

  摘要：

  The design, synthesis, and evaluation of 6 alpha-(hydroxymethyl)penicillanic acid (4) as a new mechanism-based inhibitor for the class A TEM-1 beta-lactamase is described. The design of this compound was aided by computer modeling, using the high-resolution crystal structure for the TEM-1 beta-lactamase. The molecule is believed to displace the hydrolytic water molecule (Wat-712) with its hydroxymethyl function. This interaction would impart longevity to the acyl-enzyme intermediate, accounting for the onset of inhibition, a process that results in an 11-h period for recovery of 90% of activity for the inhibited enzymes. This molecule inhibited the TEM-1 beta-lactamase rapidly, for which the kinetic parameters were evaluate. The molecule showed a partition ratio (i.e., k(cat)/k(inact)) of 28+/-2, a value which is lower than the corresponding parameter for all of the clinically used class A beta-lactamase inactivators. The design concepts outlined for 6 alpha-(hydroxymethyl)penicillanic acid as an inhibitor support the mechanistic roles proposed for Glu-166 and Wat-712 in the deacylation step for turnover chemistry by class A beta-lactamases. Furthermore, the principles that we disclose herein for the design of compound 4 as an inhibitor for beta-lactamases should be of general interest for designing specific inhibitors for any hydrolytic enzyme for which high-resolution crystal structure is available.

  DOI：

  10.1021/ja00150a003

文献信息

• Stereoselective Reduction of α-Bromopenicillanates by Tributylphosphine
  作者：Akihiro Ishiwata、Lakshmi P. Kotra、Kazuyuki Miyashita、Tsuyoshi Nagase、Shahriar Mobashery

  DOI：10.1021/ol000185e

  日期：2000.9.1

  [reaction: see text] Diastereoselective reduction of 6-bromo-6-substituted penicillanate esters has been achieved by treatment with tributylphosphine to give 6-substituted penicillanate esters. This reaction would appear to proceed through a phosphonium beta-lactam enolate species, followed by a diastereoselective protonation. This method has the advantage of being simple to carry out and it is mild

  [反应：见正文]通过用三丁基膦处理得到6-取代的青霉酸酯，已经实现了6-溴-6-取代的青霉酸酯的非对映选择性还原。该反应似乎通过through-β-内酰胺烯醇化species物种进行，随后是非对映选择性质子化。该方法的优点是易于实施，并且温和，非对映选择性高，并且应能耐受底物中的许多官能团。这些意见的含义进行了讨论。
• Design, Synthesis, and Evaluation of a Potent Mechanism-Based Inhibitor for the TEM .beta.-Lactamase with Implications for the Enzyme Mechanism
  作者：Kazuyuki Miyashita、Irina Massova、Pascale Taibi、Shahriar Mobashery

  DOI：10.1021/ja00150a003

  日期：1995.11

  The design, synthesis, and evaluation of 6 alpha-(hydroxymethyl)penicillanic acid (4) as a new mechanism-based inhibitor for the class A TEM-1 beta-lactamase is described. The design of this compound was aided by computer modeling, using the high-resolution crystal structure for the TEM-1 beta-lactamase. The molecule is believed to displace the hydrolytic water molecule (Wat-712) with its hydroxymethyl function. This interaction would impart longevity to the acyl-enzyme intermediate, accounting for the onset of inhibition, a process that results in an 11-h period for recovery of 90% of activity for the inhibited enzymes. This molecule inhibited the TEM-1 beta-lactamase rapidly, for which the kinetic parameters were evaluate. The molecule showed a partition ratio (i.e., k(cat)/k(inact)) of 28+/-2, a value which is lower than the corresponding parameter for all of the clinically used class A beta-lactamase inactivators. The design concepts outlined for 6 alpha-(hydroxymethyl)penicillanic acid as an inhibitor support the mechanistic roles proposed for Glu-166 and Wat-712 in the deacylation step for turnover chemistry by class A beta-lactamases. Furthermore, the principles that we disclose herein for the design of compound 4 as an inhibitor for beta-lactamases should be of general interest for designing specific inhibitors for any hydrolytic enzyme for which high-resolution crystal structure is available.