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1.
Daohong Liao Shaoqiang Yang Jianyu Wang Jian Zhang Benke Hong Fan Wu Prof. Dr. Xiaoguang Lei 《Angewandte Chemie (International ed. in English)》2016,55(13):4291-4295
The increase and spread of Gram‐negative bacteria that resistant are to almost all currently available β‐lactam antibiotics is a major global health problem. The primary cause for drug resistance is the acquisition of metallo‐β‐lactamases such as metallo‐β‐lactamase‐1 (NDM‐1). The fungal natural product aspergillomarasmine A (AMA), a fungal natural product, is an inhibitor of NDM‐1 and has shown promising in vivo therapeutic potential in a mouse model infected with NDM‐1‐expressing Gram‐negative bacteria. The first total synthesis and stereochemical configuration reassignment of aspergillomarasmine A is reported. The synthesis highlights a flexible route and an effective strategy to achieve the required oxidation state at a late stage. This modular route is amenable to the efficient preparation of analogues for the development of metallo‐β‐lactamase inhibitors to potentiate β‐lactam antibiotics. 相似文献
2.
The spread of antibiotic resistance in pathogenic bacteria has become one of the major concerns to public health. Improved monitoring of drug resistance is of high importance for infectious disease control. One of the major mechanisms for bacteria to overcome treatment of antibiotics is the production of β‐lactamases, which are enzymes that hydrolyze the β‐lactam ring of the antibiotic. In this study, we have developed a self‐immobilizing and fluorogenic probe for the detection of β‐lactamase activity. This fluorogenic reagent, upon activation by β‐lactamases, turns on a fluorescence signal and, more importantly, generates a covalent linkage to the target enzymes or the nearby proteins. The covalent labeling of enzymes was confirmed by SDS‐PAGE analysis and MALDI‐TOF mass spectrometry. The utility of this structurally simple probe was further confirmed by the fluorescent labeling of a range of β‐lactamase‐expressing bacteria. 相似文献
3.
Christopher T. Lohans H. T. Henry Chan Tika R. Malla Kiran Kumar Jos J. A. G. Kamps Darius J. B. McArdle Emma vanGroesen Mariska deMunnik Catherine L. Tooke James Spencer Robert S. Paton Jürgen Brem Christopher J. Schofield 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2019,131(7):2012-2016
Enzymes often use nucleophilic serine, threonine, and cysteine residues to achieve the same type of reaction; the underlying reasons for this are not understood. While bacterial d,d ‐transpeptidases (penicillin‐binding proteins) employ a nucleophilic serine, l,d ‐transpeptidases use a nucleophilic cysteine. The covalent complexes formed by l,d ‐transpeptidases with some β‐lactam antibiotics undergo non‐hydrolytic fragmentation. This is not usually observed for penicillin‐binding proteins, or for the related serine β‐lactamases. Replacement of the nucleophilic serine of serine β‐lactamases with cysteine yields enzymes which fragment β‐lactams via a similar mechanism as the l,d ‐transpeptidases, implying the different reaction outcomes are principally due to the formation of thioester versus ester intermediates. The results highlight fundamental differences in the reactivity of nucleophilic serine and cysteine enzymes, and imply new possibilities for the inhibition of nucleophilic enzymes. 相似文献
4.
A New Mechanism for β‐Lactamases: Class D Enzymes Degrade 1β‐Methyl Carbapenems through Lactone Formation
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Dr. Christopher T. Lohans Emma van Groesen Kiran Kumar Catherine L. Tooke Dr. James Spencer Prof. Dr. Robert S. Paton Dr. Jürgen Brem Prof. Dr. Christopher J. Schofield 《Angewandte Chemie (International ed. in English)》2018,57(5):1282-1285
β‐Lactamases threaten the clinical use of carbapenems, which are considered antibiotics of last resort. The classical mechanism of serine carbapenemase catalysis proceeds through hydrolysis of an acyl‐enzyme intermediate. We show that class D β‐lactamases also degrade clinically used 1β‐methyl‐substituted carbapenems through the unprecedented formation of a carbapenem‐derived β‐lactone. β‐Lactone formation results from nucleophilic attack of the carbapenem hydroxyethyl side chain on the ester carbonyl of the acyl‐enzyme intermediate. The carbapenem‐derived lactone products inhibit both serine β‐lactamases (particularly class D) and metallo‐β‐lactamases. These results define a new mechanism for the class D carbapenemases, in which a hydrolytic water molecule is not required. 相似文献
5.
Chunyang Chen Jan S. Kramer Steffen Brunst Ewgenij Proschak Gerhard K.E. Scriba 《Electrophoresis》2019,40(18-19):2375-2381
Generic in‐capillary as well as offline CE‐based enzyme assays were developed for serine‐β‐lactamases and metallo‐β‐lactamases. The hydrolysis of benzylpenicillin to benzylpenicilloic acid was analyzed using 100 mM sodium phosphate solution, pH 6.0, as a background electrolyte. In‐capillary assays employed an uncoated as well as a polyethylene oxide‐coated capillary, while the offline assays employing long end and short end injection were performed in an uncoated capillary. Using procaine hydrochloride or 4‐hydroxybenzoic acid as internal standard, the respective assays were validated with regard to linearity, LOD and LOQ, repeatability, precision, and accuracy. The assays were applied to the determination of the Michaelis‐Menten parameters Km and Vmax of Bacillus cereus penicillinase as well as New Delhi metallo‐β‐lactamase 1 and Verona integrin‐encoded metallo‐β‐lactamase 2. Furthermore, the inhibition of the enzymes by irreversible and competitive inhibitors was evaluated. Comparable data were obtained with all assays. The use of a simple substrate ensured broad applicability to the various types of β‐lactamases. 相似文献
6.
Yang Ding Zheng Li Chenchen Xu Wenjing Qin Qiong Wu Xuchun Wang Xiamin Cheng Lin Li Wei Huang 《Angewandte Chemie (International ed. in English)》2021,60(1):24-40
β‐Lactam antibiotics are generally perceived as one of the greatest inventions of the 20th century, and these small molecular compounds have saved millions of lives. However, upon clinical application of antibiotics, the β‐lactamase secreted by pathogenic bacteria can lead to the gradual development of drug resistance. β‐Lactamase is a hydrolase that can efficiently hydrolyze and destroy β‐lactam antibiotics. It develops and spreads rapidly in pathogens, and the drug‐resistant bacteria pose a severe threat to human health and development. As a result, detecting and inhibiting the activities of β‐lactamase are of great value for the rational use of antibiotics and the treatment of infectious diseases. At present, many specific detection methods and inhibitors of β‐lactamase have been developed and applied in clinical practice. In this Minireview, we describe the resistance mechanism of bacteria producing β‐lactamase and further summarize the fluorogenic probes, inhibitors of β‐lactamase, and their applications in the treatment of infectious diseases. It may be valuable to design fluorogenic probes with improved selectivity, sensitivity, and effectiveness to further identify the inhibitors for β‐lactamases and eventually overcome bacterial resistance. 相似文献
7.
Markus W. Weishaupt Stefan Matthies Prof. Dr. Peter H. Seeberger 《Chemistry (Weinheim an der Bergstrasse, Germany)》2013,19(37):12497-12503
β‐Glucans are a group of structurally heterogeneous polysaccharides found in bacteria, fungi, algae and plants. β‐(1,3)‐D ‐Glucans have been studied in most detail due to their impact on the immune system of vertebrates. The studies into the immunomodulatory properties of these glucans are typically carried out with isolates that contain a heterogeneous mixture of polysaccharides of different chain lengths and varying degrees of branching. In order to determine the structure–activity relationship of β‐(1,3)‐glucans, access to homogeneous, structurally‐defined samples of these oligosaccharides that are only available through chemical synthesis is required. The syntheses of β‐glucans reported to date rely on the classical solution‐phase approach. We describe the first automated solid‐phase synthesis of a β‐glucan oligosaccharide that was made possible by innovating and optimizing the linker and glycosylating agent combination. A β‐(1,3)‐glucan dodecasaccharide was assembled in 56 h in a stereoselective fashion with an average yield of 88 % per step. This automated approach provides means for the fast and efficient assembly of linker‐functionalized mono‐ to dodecasaccharide β‐(1,3)‐glucans required for biological studies. 相似文献
8.
《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2017,129(5):1391-1395
A general asymmetric route for the one‐step synthesis of chiral β‐branched amides is reported through the highly enantioselective isomerization of allylamines, followed by enamine exchange, and subsequent oxidation. The enamine exchange allows for a rapid and modular synthesis of various amides, including challenging β‐diaryl and β‐cyclic. 相似文献
9.
《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2017,129(14):3920-3924
Resistance to β‐lactam antibiotics mediated by metallo‐β‐lactamases (MBLs) is a growing problem. We describe the use of protein‐observe 19F‐NMR (PrOF NMR) to study the dynamics of the São Paulo MBL (SPM‐1) from β‐lactam‐resistant Pseudomonas aeruginosa . Cysteinyl variants on the α3 and L3 regions, which flank the di‐ZnII active site, were selectively 19F‐labeled using 3‐bromo‐1,1,1‐trifluoroacetone. The PrOF NMR results reveal roles for the mobile α3 and L3 regions in the binding of both inhibitors and hydrolyzed β‐lactam products to SPM‐1. These results have implications for the mechanisms and inhibition of MBLs by β‐lactams and non‐β‐lactams and illustrate the utility of PrOF NMR for efficiently analyzing metal chelation, identifying new binding modes, and studying protein binding from a mixture of equilibrating isomers. 相似文献
10.
Manoj Balu Wagh R. Shankar K. Mini T. Krishnamohan M. V. Madhubabu Abir K. Pal Sarva Jayaprakash T. Krishna Vilas Dahanukar U. K. Syam Kumar C. H. Gill 《Journal of heterocyclic chemistry》2013,50(1):49-55
A novel approach has been developed for the synthesis of β‐arylacyl/β‐heteroarylacyl‐β‐alkylidine malonates in moderate to good yields by the reaction of Stork aryl and heteroaryl enamine with β‐chloroalkylidene malonates. The reaction involves conjugate (Michael) addition of Stork enamine on β‐chloroalkylidene malonates and elimination of chloride ion. These Michael adducts were utilized as intermediates for the synthesis of highly substituted 1,4‐dialkyl‐2‐oxo‐6‐aryl/hetreoaryl‐1,2‐dihydro‐pyridine‐3‐carboxylic acid ethyl esters via 5 + 1 ring annulation protocol. 相似文献
11.
Linli Zhang Zheng Wang Zhaobin Han Kuiling Ding 《Angewandte Chemie (International ed. in English)》2020,59(36):15565-15569
A Mn‐catalyzed diastereo‐ and enantioselective hydrogenation of α‐substituted β‐ketoamides has been realized for the first time under dynamic kinetic resolution conditions. anti‐α‐Substituted β‐hydroxy amides, which are useful building blocks for the synthesis of bioactive molecules and chiral drugs, were prepared in high yields with excellent selectivity (up to >99 % dr and >99 % ee) and unprecedentedly high activity (TON up to 10000). The origin of the excellent stereoselectivity was clarified by DFT calculations. 相似文献
12.
Engineering the Stereochemistry of Cephalosporin for Specific Detection of Pathogenic Carbapenemase‐Expressing Bacteria
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Dr. Haibin Shi Dr. Yunfeng Cheng Dr. Kyung Hyun Lee Dr. Robert F. Luo Prof. Niaz Banaei Prof. Jianghong Rao 《Angewandte Chemie (International ed. in English)》2014,53(31):8113-8116
Reported herein is the design of fluorogenic probes specific for carbapenem‐resistant Enterobacteriaceae (CRE) and they were designed based on stereochemically modified cephalosporin having a 6,7‐trans configuration. Through experiments using recombinant β‐lactamase enzymes and live bacterial species, these probes demonstrate the potential for use in the specific detection of carbapenemases, including metallo‐β‐lactamases in active bacterial pathogens. 相似文献
13.
Christopher Selleck Prof. James A. Larrabee Assoc. Prof. Jeffrey Harmer Assoc. Prof. Luke W. Guddat Dr. Nataša Mitić Waleed Helweh Prof. David L. Ollis Dr. Whitney R. Craig Prof. David L. Tierney Dr. Marcelo Monteiro Pedroso Prof. Gerhard Schenk 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(49):17704-17714
Antibiotic resistance has emerged as a major threat to global health care. This is largely due to the fact that many pathogens have developed strategies to acquire resistance to antibiotics. Metallo‐β‐lactamases (MBL) have evolved to inactivate most of the commonly used β‐lactam antibiotics. AIM‐1 is one of only a few MBLs from the B3 subgroup that is encoded on a mobile genetic element in a major human pathogen. Here, its mechanism of action was characterised with a combination of spectroscopic and kinetic techniques and compared to that of other MBLs. Unlike other MBLs it appears that AIM‐1 has two avenues available for the turnover of the substrate nitrocefin, distinguished by the identity of the rate‐limiting step. This observation may be relevant with respect to inhibitor design for this group of enzymes as it demonstrates that at least some MBLs are very flexible in terms of interactions with substrates and possibly inhibitors. 相似文献
14.
β‐Amino acid N‐carboxy anhydrides (β‐NCAs) are rarely used in the synthesis of β‐peptides, which is due mainly to the poor availability of these potentially useful substrates. Herein, we describe the heretofore challenging synthesis of β‐NCAs via a single‐step, rapid, and mild formation using pH flash switching and flash dilution, which are aspects of micro‐flow technology. We synthesized 15 β‐NCAs in good to excellent yields that included acid‐labile β‐NCAs that cannot be readily synthesized using the conventional Leuchs approach. Scaled‐up synthesis using this process can be readily achieved via continuous operation. 相似文献
15.
Total Synthesis of Aspergillomarasmine A and Related Compounds: A Sulfamidate Approach Enables Exploration of Structure–Activity Relationships
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Dr. Silvia A. Albu Dr. Kalinka Koteva Dr. Andrew M. King Salma Al‐Karmi Prof. Gerard D. Wright Prof. Alfredo Capretta 《Angewandte Chemie (International ed. in English)》2016,55(42):13259-13262
The fungal secondary metabolite aspergillomarasmine A (AMA) has recently been identified as an inhibitor of metallo‐β‐lactamases NDM‐1 and VIM‐2. Described herein is an efficient and practical route to AMA and its related compounds by a sulfamidate approach. In addition, a series of derivatives has been prepared and tested for biological activity in an effort to explore preliminary structure activity relationships. While it was determined that natural LLL isomer of AMA remains the most effective inactivator of NDM‐1 enzyme activity both in vitro and in cells, the structure is highly tolerant of the changes in the stereochemistry at positions 3, 6, and 9. 相似文献
16.
Shimon Farber Bernard S. Green Abraham J. Domb 《Journal of polymer science. Part A, Polymer chemistry》2009,47(20):5534-5542
An efficient novel method for the synthesis of a covalent molecularly imprinted polymer (MIP) highly specific to β‐estradiol have been developed. MIP prepared by both covalent and non covalent techniques, demonstrated high selectivity toward β‐estradiol. MIPs were synthesized by radical polymerization of 17‐β‐estradiol 4‐vinyl‐benzene carboxyl or sulfonyl esters used as covalent functional monomers, methacrylic acid as noncovalent functional monomer, ethylene glycol dimethacrylate as crosslinking agent, and acetonitrile as swelling and porogenic component. Almost 35% (w/w) of 17‐β‐estradiol was successfully removed from the polymer network by basic hydrolysis. The binding ability of MIP was 10.73 μg/mg MIP following removal of 17‐β‐estradiol in the 2 mg/mL β‐estradiol solution. Selective rebinding of β‐estradiol toward MIP was tested in the presence of competitive binders including estrone, 19‐nortestosterone, epiandrosterone, and cholesterol. Estrone having closest similar chemical structure to β‐estradiol exhibited only 0.6 μg/mg MIP competitive binding, being exposed to equivalent concentrations. Moreover, other competitive steroids demonstrated negligible affinity toward MIP indicating high selectivity of novel MIP system toward β‐estradiol. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 5534–5542, 2009 相似文献
17.
Palladium‐Catalyzed Oxidative Carbonylation of N‐Allylamines for the Synthesis of β‐Lactams
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Wu Li Dr. Chao Liu Prof. Heng Zhang Keyin Ye Guanghui Zhang Wangzheng Zhang Zhengli Duan Prof. Shuli You Prof. Aiwen Lei 《Angewandte Chemie (International ed. in English)》2014,53(9):2443-2446
β‐Lactam scaffolds are considered to be ideal building blocks for the synthesis of nitrogen‐containing compounds. A new palladium‐catalyzed oxidative carbonylation of N‐allylamines for the synthesis of α‐methylene‐β‐lactams is reported. DFT calculations suggest that the formation of β‐lactams via a four‐membered‐ring transition state is favorable. 相似文献
18.
《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2017,129(8):2091-2095
The catalytic asymmetric synthesis of both α‐substituted and α,α‐disubstituted (quaternary) β‐tetralones through direct α‐functionalization of the corresponding β‐tetralone precursor remains elusive. A designed Brønsted base‐squaramide bifunctional catalyst promotes the conjugate addition of either unsubstituted or α‐monosubstituted β‐tetralones to nitroalkenes. Under these reaction conditions, not only enolization, and thus functionalization, occurs at the α‐carbon atom of the β‐tetralone exclusively, but adducts including all‐carbon quaternary centers are also formed in highly diastereo‐ and enantioselective manner. 相似文献
19.
Recyclable Hypervalent‐Iodine‐Mediated Dehydrogenative α,β′‐Bifunctionalization of β‐Keto Esters Under Metal‐Free Conditions
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Ya‐Nan Duan Li‐Qian Cui Lin‐Hong Zuo Chi Zhang 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(37):13052-13057
We have developed a method for recyclable hypervalent‐iodine‐mediated direct dehydrogenative α,β′‐ bifunctionalization of β‐ketoesters and β‐diketones under metal‐free conditions, which affords a straightforward way to synthesize benzo‐fused 2,3‐dihydrofurans. This efficient, mild method, which has a wide substrate scope and good functional‐group tolerance, was used for the multistep synthesis of the protected aglycone of a naturally occurring phenolic glycoside. A mechanism involving Michael addition to an enone intermediate and subsequent oxidative cyclization is proposed. 相似文献
20.
The previously described chiral 2‐acyloxathianes 5 (Scheme I) are used in two different enantioselective syntheses of γ‐butyrolactones. In one synthesis, Grignard addition, cleavage and reduction to carbinols RR'C(OH)CH2OH is followed by tosylation, malonate homologation, lactonization, and removal of the carbomethoxy group to give optically active γ‐lactones. A modification of this synthesis (Scheme I) leads to optically active α‐methylene‐γ‐lactones. In the second synthesis, reaction of a bromomagnesium enolate with ketones 5 leads to β‐hydroxyesters, which, by appropriate sequences of reduction and cleavage (Scheme II) are converted to optically active α‐ or β‐hydroxy‐γ‐lactones. 相似文献