(6R,7R)-4-methoxybenzyl-3-(chloromethyl)-8-oxo-7-(2-(thiophen-2-yl)acetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | 101182-25-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 内酰胺类
• 英文名称: (6R,7R)-4-methoxybenzyl-3-(chloromethyl)-8-oxo-7-(2-(thiophen-2-yl)acetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate
• 英文别名: p-methoxybenzyl (6R,7R)-3-chloromethyl-7β-(2-thienylacetamido)-3-cephem-4-carboxylate；p-methoxybenzyl 7β-(2-thienylacetamido)-3-(chloromethyl)-3-cephem-4-carboxylate；p-methoxybenzyl (6R,7R)-3-chloromethyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate；(4-methoxyphenyl)methyl (6R,7R)-3-(chloromethyl)-8-oxo-7-[(2-thiophen-2-ylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate
• CAS: 101182-25-6
• 化学式: C₂₂H₂₁ClN₂O₅S₂
• 分子量: 493.004
• InChiKey: VLBYSBPWXHXHEK-WIYYLYMNSA-N

物化性质

• 沸点：
  764.6±60.0 °C(Predicted)
• 密度：
  1.47±0.1 g/cm3(Predicted)
• 溶解度：
  溶于二氯甲烷

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  32
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  139
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (6R,7R)-4-methoxybenzyl-3-(chloromethyl)-8-oxo-7-(2-(thiophen-2-yl)acetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 在 potassium trimethylsilonate 、 苯甲醚 、 三氟乙酸 、 sodium iodide 作用下， 以 二氯甲烷 、 氯仿 、 二甲基亚砜 、 乙腈 、 丁酮 为溶剂， 反应 30.25h， 生成 头孢硝噻吩
  参考文献：
  名称：

  A Practical Synthesis of Nitrocefin

  摘要：

  Nitrocefin is a key reagent for high and low throughput assays of the activities of penicillin-binding proteins (PBPs) and beta-lactamases, the former used for discovery of antibiotics and the latter for inhibitors of resistance determinants for beta-lactam antibiotics. This compound is commercially available but is prohibitively expensive because of the circuitous routes to its synthesis. We describe herein a three-step synthesis of nitrocefin that gives an overall yield of 44%. This is a practical route to the synthesis of this key reagent for drug discover.

  DOI：

  10.1021/jo0487395
• 作为产物：
  描述：

  p-methoxybenzyl 7β-(2-thienylacetamido)-3-(hydroxymethyl)-3-cephem-4-carboxylate 在 吡啶 、 三光气 作用下， 以 四氢呋喃 为溶剂， 反应 0.5h， 以81%的产率得到(6R,7R)-4-methoxybenzyl-3-(chloromethyl)-8-oxo-7-(2-(thiophen-2-yl)acetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate
  参考文献：
  名称：

  Facile chloride substitution of activated alcohols by triphosgene: application to cephalosporin chemistry

  摘要：

  DOI：

  10.1021/jo00025a046

文献信息

• Design and synthesis of a β-lactamase activated 5-fluorouracil prodrug
  作者：Ryan M. Phelan、Marc Ostermeier、Craig A. Townsend

  DOI：10.1016/j.bmcl.2008.12.057

  日期：2009.2

  An efficient synthesis of a 5-fluorouracil-cephalosporin prodrug is described for use against colorectal and other cancers in antibody and gene-directed therapies. The compound shows stability in aqueous media until specifically activated by β-lactamase (βL). The kinetic parameters of the 5-fluorouracil-cephalosporin conjugate were determined in the presence of Enterobacter cloacae P99 βL (ECl βL)

  描述了一种有效合成的 5-氟尿嘧啶-头孢菌素前药，用于在抗体和基因导向疗法中对抗结直肠癌和其他癌症。该化合物在水性介质中表现出稳定性，直到被 β-内酰胺酶 (βL) 特异性激活。5-氟尿嘧啶-头孢菌素偶联物的动力学参数在阴沟肠杆菌P99 βL (ECl βL)存在下测定，显示K m  = 95.4 μM 和V max  = 3.21 μMol min -1  mg -1。该数据与已报道的相关系统相比具有优势，并且能够在体外和体内测试该前药对抗癌细胞系。
• Synthesis of cephalosporin-3′-diazeniumdiolates: biofilm dispersing NO-donor prodrugs activated by β-lactamase
  作者：Nageshwar Rao Yepuri、Nicolas Barraud、Nasim Shah Mohammadi、Bharat G. Kardak、Staffan Kjelleberg、Scott A. Rice、Michael J. Kelso

  DOI：10.1039/c3cc40869h

  日期：——

  Use of biofilm dispersing NO-donor compounds in combination with antibiotics has emerged as a promising new strategy for treating drug-resistant bacterial biofilm infections. This paper details the synthesis and preliminary evaluation of six cephalosporin-3'-diazeniumdiolates as biofilm-targeted NO-donor prodrugs. Each of the compounds is shown to selectively release NO following reaction with the

  生物膜分散NO供体化合物与抗生素的结合使用已成为治疗耐药细菌生物膜感染的有前途的新策略。本文详细介绍了六种头孢菌素3'-二氮杂二醇盐作为生物膜靶向NO供体前药的合成和初步评估。已显示每种化合物在与细菌特异性酶β-内酰胺酶反应后选择性释放NO，并在体外触发铜绿假单胞菌生物膜的分散。
• Design and Biological Evaluation of Cephalosporin Based Metallo-β-lactamase (MBL) Inhibitors#
  作者：Shaan Patel、Pradip Jadav、Rajesh Bahekar、Kumargurubaran Nagaswamy、Kasinath Viswanathan、Purvi Vyas、Poonam Giri、Sachchidanand S、Mukul Jain

  DOI：10.2174/0115701808287192240415062148

  日期：2024.4.24

  enzyme pose a serious threat to human life. MBLs depend on active site zinc for their hydrolytic activity; hence, the investigation of zinc chelators emerged as an attractive strategy for the development of potent MBL inhibitors. Methods: To prove that such chelators selectively target MBLs, in the present investigation, novel cephalosporins based MBL inhibitors (Cef-MBLi) were designed as a conjugate

  背景：金属-β-内酰胺酶（MBL）引起的微生物耐药性的普遍存在对人类生命构成严重威胁。 MBL 的水解活性依赖于活性位点锌；因此，锌螯合剂的研究成为开发有效 MBL 抑制剂的一个有吸引力的策略。方法：为了证明此类螯合剂选择性地靶向 MBL，在本研究中，新型基于头孢菌素的 MBL 抑制剂 (Cef-MBLi) 被设计为头孢菌素与有效的锌结合剂 8-硫代喹啉 (8-TQ) 的缀合物。结果：Cef-MBLi 仅在 Veronaintegron 编码的金属-β-内酰胺酶 2 (VIM-2) 细菌酶存在的情况下通过水解裂解机制显示结合物的位点特异性释放。总共制备、表征了 6 种新化学实体（NCE）（4a-e 和 6f），并进行了体外研究。结论：在测试的 NCE 中，4c 对 VIM-2 酶表现出有效的 MBL 抑制活性。
• Novel fluorescent cephalosporins: Synthesis, antimicrobial activity and photodynamic inactivation of antibiotic resistant bacteria
  作者：Jian-Min Xiao、Lei Feng、Li-Sheng Zhou、Hui-Zhou Gao、Yi-Lin Zhang、Ke-Wu Yang

  DOI：10.1016/j.ejmech.2012.11.019

  日期：2013.1

  Two novel fluorescent cephalosporins, TCA and TBCA, were synthesized and characterized by H-1 NMR, C-13 NMR, UV-vis, and fluorescence spectroscopies. Biological activity assays demonstrated that TCA inactivated a Klebsiella pneumonia strain that expressed extended-spectrum beta-lactamases. Incubation of 6 mu M TCA with K. pneumonia cultures resulted in cell death for 84% of the cells after 126 J/cm(2) of light irradiation. In vitro, TCA exhibited a MIC = 0.5 mu g/mL with Staphylococcus aureus. Kinetic evaluation revealed that TCA and TBCA were substrates for B1 and B3 subclass metallo-beta-lactamases. TBCA exhibited stronger binding affinities to the Gram-positive bacterial strains MRSA1, MRSA2, and S. aureus with value of 2.95-6.59 mu M per 10(8) cells/mL. (C) 2012 Elsevier Masson SAS. All rights reserved.
• [EN] BETA-LACTAM-CANNABINOID CONJUGATE MOLECULES<br/>[FR] MOLÉCULES CONJUGUÉES DE BÊTA-LACTAME-CANNABINOÏDE
  申请人：DIVERSE BIOTECH INC

  公开号：WO2020263975A1

  公开（公告）日：2020-12-30

  This disclosure provides multifunctional conjugate molecules in which at least one β-lactam antibiotic is covalently attached to a cannabinoid by means of a linker. The disclosed conjugate molecules are designed to deliver therapeutic benefits as intact molecules, with release of the cannabinoid upon binding of the β-lactam antibiotic to its target conveying further therapeutic benefits, and can be used to treat bacterial infections and other disorders.