Synthesis of a new chiral oxazolidinone auxiliary based on d-xylose and its application to the Staudinger reaction

The synthesis of a new chiral oxazolidinone auxiliary based on d-xylose is described which is employed in diastereoselective Staudinger-type β-lactam syntheses. Using 2-chloro-1-methylpyridinium iodide as the dehydrating reagent, the reaction of auxiliary tethered acetic acid with acyclic or cyclic imines gave the desired β-lactams in good yields with excellent cis- or trans-selectivity depending on the geometry of the imine. X-Ray structure determination of one of the obtained compounds corroborated the absolute configuration for all cis products.     

Quinolactacin Biosynthesis Involves Non-Ribosomal-Peptide-Synthetase-Catalyzed Dieckmann Condensation to Form the Quinolone-γ-lactam Hybrid

Quinolactacins are novel fungal alkaloids that feature a quinolone-γ-lactam hybrid, which is a potential pharmacophore for the treatment of cancer and Alzheimer's disease. Herein, we report the identification of the quinolactacin A2 biosynthetic gene cluster and elucidate the enzymatic basis for the formation of the quinolone-γ-lactam structure. We reveal an unusual β-keto acid (N-methyl-2-aminobenzoylacetate) precursor that is derived from the primary metabolite l -kynurenine via methylation, oxidative decarboxylation, and amide hydrolysis reactions. In vitro assays reveal two single-module non-ribosomal peptide synthetases (NRPs) that incorporate the β-keto acid and l -isoleucine, followed by Dieckmann condensation, to form the quinolone-γ-lactam. Notably, the bioconversion from l -kynurenine to the β-keto acid is a unique strategy employed by nature to decouple R*-domain-containing NRPS from the polyketide synthase (PKS) machinery, expanding the paradigm for the biosynthesis of quinolone-γ-lactam natural products via Dieckmann condensation.     

Synthesis of highly functionalized β-lactam substituted pyrroloisoquinoline and indolizinoindole system by sequential intermolecular 1,3-dipolar cycloaddition reaction and Pictet-Spengler cyclization

Synthesis of novel pyrroloisoquinoline and indolizinoindole derivatives with β-lactam unit has been achieved by sequential intermolecular 1,3-dipolar cycloaddition reaction and Pictet-Spengler cyclization. The azomethine ylide derived from β-lactam imine of α-amino ester in the presence of silver acetate reacted with nitrostyrenes to give pyrrolidinyl β-lactam, which underwent Pictet-Spengler cyclization in presence of trifluoroacetic acid to give pyrroloisoquinolines and indolizinoindoles.     

Cephem-Pyrazinoic Acid Conjugates: Circumventing Resistance in Mycobacterium tuberculosis

Tuberculosis (TB) is a leading source of infectious disease mortality globally. Antibiotic-resistant strains comprise an estimated 10 % of new TB cases and present an urgent need for novel therapeutics. β-lactam antibiotics have traditionally been ineffective against M. tuberculosis (Mtb), the causative agent of TB, due to the organism's inherent expression of β-lactamases that destroy the electrophilic β-lactam warhead. We have developed novel β-lactam conjugates, which exploit this inherent β-lactamase activity to achieve selective release of pyrazinoic acid (POA), the active form of a first-line TB drug. These conjugates are selectively active against M. tuberculosis and related mycobacteria, and activity is retained or even potentiated in multiple resistant strains and models. Preliminary mechanistic investigations suggest that both the POA “warhead” as well as the β-lactam “promoiety” contribute to the observed activity, demonstrating a codrug strategy with important implications for future TB therapy.     

Theoretical calculations of β-lactam antibiotics. III. AM1, MNDO,and MINDO/3 calculations of hydrolysis of β-lactam compound (azetidin-2-one ring)

Semiempirical AM1, MINDO/3, and MNDO methods have been used in the study of the alkaline hydrolysis of β-lactam antibiotics through a base-catalyzed, acyl-cleavage, bimolecular mechanism. In this work, the hydroxyl ion has been chosen as nucleophilic agent and the azetidin-2-one ring like a model of β-lactam antibiotic. The MINDO/3 method does not predict correctly the energies of small rings. This, together with the fact that, like MNDO, it cannot detect the occurrence of hydrogen bonds, gives rise to uncertain estimates of energy barriers. The AM1 method can be considered the most suitable for studying the hydrolysis of β-lactam compounds.     

Theoretical Calculations of β-Lactam Antibiotics. Part VI. AM1 calculations of alkaline hydrolysis of clavulanic acid

The gas-phase basic hydrolysis of clavulanic acid ( a ) was studied by using the AM1 semi-empirical method. The results obtained show that the hydroxyethylidene side chain at C(2) is pivotal to the stability of the different reaction products involved. The products with an open oxazolidine ring are more stable than those with a closed ring fused to the β-lactam ring. This behaviour differs from that of penicillins and cephalosporins where the most stable degradation products are those with an intact thiazolidine or dihydrothiazine ring, respectively, fused to the β-lactam ring. The different chemical reactivity of clavulanic acid relative to penicillins and cephalosporins could explain the disparate behaviour of the latter two types of compound towards β-lactamases. Once the acyl-enzyme intermediate of clavulanic acid has been formed, it can evolve with cleavage of the oxazolidine ring to form a difficult to deacylate compound.     

New -lactam antibiotics. Preparation of 7-aminocephalocillanic acid

‘7-aminocephalocillanic acid’ 1 , an intermediate for the preparation of new β-lactam antibiotics was prepared by transforming the β-lactam carbinol 2a to the phosphorane 9a through several steps. Oxydation of 9a with DMSO/Ac₂O led directly to the cyclized ester 11a , which has been converted into 1 by known methods.     

Design and stereoselective synthesis of novel β-lactone and β-lactams as potent anticancer agents on breast cancer cells

To produce a novel class of anticancer compounds, an efficient method for synthesizing novel β-lactone and β-lactam frameworks was developed based on the reaction of a new ketene with C=O and C=N bonds. Functionalized 2-azetidinones were efficiently synthesized by employing 2,4-dichlorophenoxylketene, which was generated in situ. The reaction of the ketene with aldehydes was not successful and in all cases except for 4-nitrobenzaldehyde, a rearranged dimer of the ketene was obtained as a lactone. Anticancer cellular activity of all new β-lactams and lactones on breast cancer cells was studied. All new synthesized compounds exhibited potential anticancer activity which may guarantee their future application in moderate chemotherapy.     

Binding of β-lactam antibiotics to a bioinspired dizinc complex reminiscent of the active site of metallo-β-lactamases

Metallo-β-lactamases (mβls) cause bacterial resistance toward a broad spectrum of β-lactam antibiotics by catalyzing the hydrolytic cleavage of the four-membered β-lactam ring, thus inactivating the drug. Minutiae of the mechanism of these enzymes are still not well understood, and reports about binding studies of the substrates to the enzymes as well as to synthetic model systems are rare. Here we report a new pyrazolate-based bioinspired dizinc complex (1) reminiscent of the active site of binuclear mβls. Since 1 does not mediate hydrolytic degradation of β-lactams, the binding of a series of common β-lactam antibiotics (benzylpenicillin, cephalotin, 6-aminopenicillanic acid, ampicillin) as well as the inhibitor sulbactam and the simplest β-lactam, 2-azetidinone, to the dizinc core of 1 could now be studied in detail by NMR and IR spectroscopy as well as mass spectrometry. X-ray crystallographic information was obtained for 1 and its complexes with 2-azetidinone (2) and sulbactam (3); the latter represents the first structurally characterized dizinc complex with a bound β-lactam drug. While 2-azetidinone was found deprotonated and bridging in the clamp of the two zinc ions in 2, in 3 and all other cases the substrates preferentially bind via their carboxylate group within the bimetallic pocket. The relevance of this binding mode for mβls and consequences for the design of functional model systems are discussed.     

Organometallic derivatives of penicillins and cephalosporins a new class of semi-synthetic antibiotics

Novel semi-synthetic derivatives of penicillin and cephalosporin have been prepared in which the conventional phenyl or heteroaromatic group has been replaced by a ferrocene moiety, and in which the metal atom is in close proximity to the β-lactam ring of the antibiotic; several of the compounds exhibit high antibiotic activity and others are potent β-lactamase inhibitors.     

Modeling β-lactam interactions in aqueous solution through combined quantum mechanics–molecular mechanics methods

In this article, we have carried out a series of theoretical computations intended to analyze the interactions of β-lactam compounds in aqueous solution. The final aim is to rationalize the influence of the medium on β-lactam antibiotics reactivity. In particular, the hydrolysis reaction has been studied because of the considerable interest due to its relationship with resistance mechanisms developed by bacteria. The study is extended to the simplest β-lactam molecule, propiolactam or 2-azetidinone, and to the corresponding hydroxylated complex (resulting from the addition of a hydroxyl anion to the carbonyl group) that plays a crucial role in hydrolysis processes. Molecular Dynamics simulations have been carried out using a hybrid quantum mechanics–molecular mechanics potential: the solute is described using the density functional theory, whereas water solvent molecules are treated classically. This represents a sophisticated computational level which, compared to usual force-field simulations, has the advantage of allowing a detailed analysis of solute's electronic properties. The discussion of results is focused on the role played by solute–solvent hydrogen bonds and solvent fluctuations on solute's structure. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 1401–1411, 1999     

Ab initio study of β-lactam antibiotics. II. Potential energy surface for the amidic CN bond breaking in the 3-cephem + OH− reaction and comparison with the β-lactam + OH− reaction

The potential energy surface for the β-lactam amidic CN bond breaking in the 3-cephem + OH^? reaction was investigated by using the ab initio Hartree—Fock method with a 9s6p/7s3p/3s basis set. The investigated reaction is a model of the reaction between an antibiotic cephalosporin and an enzymatic nucleophilic group, this last reaction being related to the mode of action of β-lactam antibiotics. The minimum-energy reaction path is characterized by a tetrahedral intermediate ≈ 116 kcal mol^?1 more stable than the reagents, by a barrier which corresponds to the partial breaking of the amidic bond and is ≈ 7 kcal mol^?1 above the intermediate and by a product ≈ 31 kcal mol^?1 more stable than the intermediate. The analysis of the wavefunction along the reaction path and the comparison with the β-lactam + OH^? reaction pointed out the role of electron-withdrawing groups on the height of the barrier and the role of intramolecular hydrogen bonds on the structure and energy of the product. The calculations suggest a model of the antibiotic activity of cephalosporins which is compared with previous qualitative pictures.     

Kinetic Study on Cephamycin C Degradation

Cephamycin C (CepC) is a β-lactam antibiotic that belongs to the cephalosporin class of drugs. This compound stands out from other cephalosporins for its greater resistance to β-lactamases, which are enzymes produced by pathogenic microorganisms that present a major mechanism of bacterial resistance to β-lactam antibiotics. Cephamycin C is produced by the bacterium Streptomyces clavuligerus. Knowledge about the stability of the compound under different values of pH is important for the development of the process of production, extraction, and purification aimed at obtaining higher yields. Therefore, the stability of cephamycin C under different pH levels (2.2, 6.0, 7.0, 7.6, and 8.7) at 20 °C was evaluated in this study. Ultrafiltered broth from batch fermentations of S. clavuligerus was used in the trials. The results indicated that cephamycin C is a more stable compound than other β-lactam compounds such as penicillin and clavulanic acid. A higher degradation rate was observed at very acidic or basic pH levels, while this rate was lower at quasi-neutral pH levels. After 100 h of trial, the initial CepC showed 46 % degradation at pH 2.2, 71 % degradation at pH 8.7, and varied from 15 to 20 % at quasi-neutral pH levels.     

β-Lactam ring stability and antibacterial potency: A novel eigenvalue problem

Low inoculum potency data in vitro for 16 clinical β-lactam antibiotics have been analyzed, and a physical model for interpreting the results of a number of bacterial strains has been derived. An analytic criterion for performing a unitary transformation on the potency data is developed following the identification of a physical vector present within the data which is attributable to an activation energy required for the transport of the β-lactam into a biological membrane. This vector has inverse slope relations in Gram positive and Gram negative bacteria and provides the basis for the analytic criterion for the unitary transformation. Compounds with similar potency spectra which differ only in the absolute magnitude of their effect will possess similar transport properties. It is shown that a slow rate of membrane entry for the β-lactam has overriding consequences on differences in fast rates of binding to the target enzymes and to β-lactamases, and a second primary vector is established directly from the biological data related to the ease of β-lactam ring opening. This vector offers precise evidence for testing the solvational and theoretical requirements for predicting the biological stability of novel β-lactam ring compounds.     

Synthesis and Steric Structure of 1, 5-Benzothiazepine-Phenyl-β-Lactams

l,5-BenzothiazepinesIpossesspotentialbiologicalactivitives.'-'Cycloadditionreactionsofthecompoundswithacidhandespermittheconstructionofnewcyclicsystemf0-lactamring.The0-lactammoietymaymodifythebiologicalactivityofi,5-benzothiazepinesormaybringneweffe...     

Biosensor analysis of penicillin G in milk based on the inhibition of carboxypeptidase activity

The β-lactam antibiotics, including penicillins, are the most important antimicrobial substances used for mastitis treatment. Consequently, this is also the most frequently occurring type of antibiotic residues in milk. Today, in addition to the traditional microbial inhibitor tests, rapid and sensitive receptor and immunoassays are used in residue control. Due to the limitations in throughput capacity of these tests, recent applications of automated biosensor technology in food analysis are of great interest.A surface plasmon resonance (SPR)-based biosensor (Biacore) was used to design an inhibition assay to detect β-lactam antibiotics in milk. A microbial receptor protein with carboxypeptidase activity was used as detection molecule. One advantage of using this receptor protein over antibodies that are more commonly used is that only the active, intact β-lactam structure is recognized, whereas most antibodies detect both active and inactive forms. In the presence of β-lactam antibiotics the formation of a stable complex between receptor protein and antibiotic inhibits the enzymatic activity of the protein. The decrease in enzymatic activity was measured using an antibody against the degraded substrate and penicillin G in milk samples was quantitatively determined. The limit of detection of the assay for penicillin G was determined to 2.6 μg kg⁻¹ for antibiotic-free producer milk, which is below the European maximum residue limit (MRL) of 4 μg kg⁻¹. The coefficient of variation at 4 μg kg⁻¹ penicillin G, ranged between 7.3 and 16% on three different days.     

3-(3-叔丁氧基)丁二酰亚胺基单环β-内酰胺衍生物的合成

从苹果酸出发, 经过一系列反应得到3-(3-叔丁氧基)丁二酰亚胺乙酰氯. 3-(3-叔丁氧基)丁二酰亚胺乙酰氯和含不同取代基的Schiff碱1a～1h反应得到8个新的3-(3-叔丁氧基)丁二酰亚胺基单环β-内酰胺衍生物2a～2h, 化合物2a～2h的结构经IR, ¹H NMR, MS和元素分析所确证.     

Co2(CO)8-induced domino reactions of ethyl diazoacetate, carbon monoxide and ferrocenylimines leading to 2-(1-ferrocenyl-methylidene)-malonic acid derivatives

Novel 2-(1-ferrocenyl-methylidene)-malonic acid derivatives are obtained upon reacting ethyl diazoacetate, carbon monoxide and ferrocenylimines in the presence of Co₂(CO)₈ as catalyst under mild conditions. Presumably, the reaction involves three steps taking place in a domino fashion, (i) carbonylation of ethyl diazoacetate leading to a ketene derivative, (ii) [2+2] cycloaddition of the ketene with the ferrocenylimine present in the reaction mixture resulting in the formation of a β-lactam and (iii) N(1)-C(4) cleavage of the β-lactam ring. In most cases, 2-(1-ferrocenyl-methylidene)-malonic acid derivatives are obtained as a separable mixture of E- and Z-isomers in ratios depending on the structure of the imine component.     

γ-Lactam analogues of penicillanic and carbapenicillanic acids

Synthesis and biological activity of γ-lactam analogues of penicillanic and carboapenicillanic acids, and the sodium periodate mediated rearrangement of pyrrolidine-2,3-diones are described. 1,3- Dipolar addition of cyclic nitrone (6) and methyl acrylate afforded the bicyclic adducts (7a) and (7b). Reductive cleavage of the N-O bond and subsequent cyclisation of a regioisomer (11a) gave the γ-lactams (12a) and (12b) in a ratio of 85 : 15. They are transformed to the carbapenam analogues (1)-(4). Their stereochemistry was assigned according to the X-ray structure of the γ-lactam (12b). Benzyl 6-oxopenicillanate (20) was directly transformed to the γ-lactam analogue (5) $\text{via}$ a novel ring expansion. These synthetic analogues did not show antibiotic activity or β-lactamase inhibition. Treatment of pyrro1idine-2,3-diones (25a) and (25b) with sodium periodate gave ring contracted β-lactams (26a) and (26b) respectively. Similar treatment of (27) followed by diazomethane afforded an unexpected spiro epoxide.