4-Nitrobenzyl 6,6-dibromopenicillanate | 98510-71-5

• 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: 4-Nitrobenzyl 6,6-dibromopenicillanate
• 英文别名: P-Nitrobenzyl-6,6-dibromopenicillinate；(4-nitrophenyl)methyl (2S,5R)-6,6-dibromo-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate
• CAS: 98510-71-5
• 化学式: C₁₅H₁₄Br₂N₂O₅S
• 分子量: 494.161
• InChiKey: PWPAEVUYDSBPBY-GXFFZTMASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.466
• 拓扑面积：
  118
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-Nitrobenzyl 6,6-dibromopenicillanate 在 palladium on activated charcoal 三丁基膦 、 sodium phosphate buffer 、 甲基溴化镁 、 氢气 作用下， 以 甲醇 、 水 为溶剂， 反应 4.0h， 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 、 6,6-二溴青霉烷酸 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以67%的产率得到4-Nitrobenzyl 6,6-dibromopenicillanate
  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

• Phase-Transfer Esterification of the Alkali Metal Salts of Cephalosporins and Penicillins
  作者：Iñaki Ganboa、Claudio Palomo

  DOI：10.1055/s-1986-31474

  日期：——

  Cephalosporins and penicillins can be converted into their alkyl esters in high yields by reaction of their solid sodium or potassium salts with alkyl bromides in acetonitrile in the presence of crown ethers as phase-transfer catalysts.

  在冠醚作为相转移催化剂的存在下，头孢菌素类和青霉素类的固体钠盐或钾盐与烷基溴化物在乙腈中发生反应，可以高产率地转化为它们的烷基酯。
• 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。
• Ring-opening process for preparing azetidinone intermediates
  申请人：Farmitalia Carlo Erba S.p.A.

  公开号：US04771134A1

  公开（公告）日：1988-09-13

  Compounds of formula I ##STR1## wherein R.sub.1 and R.sub.2 is each H, halo or an organic group, R.sub.3 is H or organic group, n=1 or 2, M is a heavy mono- or divalent metal, or M.sub.2 A wherein M.sub.2 is a heavy divalent metal and A is an organic or inorganic group, are prepared by treating a starting penicillin in a solvent with a salt of M.sub.1 or M.sub.2 A in the presence of a base at a temperature of from -70.degree. to 100.degree. C.

  化合物的化学式为I ##STR1## 其中R.sub.1和R.sub.2均为H，卤素或有机基团，R.sub.3为H或有机基团，n=1或2，M为重单价或双价金属，或M.sub.2 A，其中M.sub.2为重双价金属，A为有机或无机基团，通过在溶剂中使用M.sub.1或M.sub.2 A的盐，在碱存在下，在-70℃至100℃的温度下处理起始青霉素而制备得到。
• Penicillin Derivatives Inhibit the SARS-CoV-2 Main Protease by Reaction with Its Nucleophilic Cysteine
  作者：Tika R. Malla、Lennart Brewitz、Dorian-Gabriel Muntean、Hiba Aslam、C. David Owen、Eidarus Salah、Anthony Tumber、Petra Lukacik、Claire Strain-Damerell、Halina Mikolajek、Martin A. Walsh、Christopher J. Schofield

  DOI：10.1021/acs.jmedchem.1c02214

  日期：2022.6.9

  nucleophilic serine and cysteine proteases. We describe the synthesis of penicillin derivatives which are potent Mpro inhibitors and investigate their mechanism of inhibition using mass spectrometric and crystallographic analyses. The results suggest that β-lactams have considerable potential as Mpro inhibitors via a mechanism involving reaction with the nucleophilic cysteine to form a stable acyl–enzyme

  SARS-CoV-2 主要蛋白酶 (M pro ) 是治疗 COVID-19 的药物化学靶标。鉴于β-内酰胺作为细菌亲核酶抑制剂的临床功效，它们作为病毒亲核丝氨酸和半胱氨酸蛋白酶的抑制剂引起了人们的兴趣。我们描述了青霉素衍生物的合成，它们是有效的 M pro抑制剂，并使用质谱和晶体分析研究了其抑制机制。结果表明，β-内酰胺作为 M pro抑制剂具有相当大的潜力，其机制涉及与亲核半胱氨酸反应形成稳定的酰基-酶复合物，如晶体学分析所示。结果强调了利用 β-内酰胺和相关酰化剂的亲核催化抑制病毒蛋白酶的潜力。
• Alpegiani, Marco; Bodeschi, Angelo; Bissolino, Pierluigi, Heterocycles, 1990, vol. 31, # 4, p. 617 - 628
  作者：Alpegiani, Marco、Bodeschi, Angelo、Bissolino, Pierluigi、Visentin, Giuseppina、Zarini, Franco、et al.

  DOI：——

  日期：——