Lactam Compounds Research Articles

Construction of Six-Membered Lactam and Lactone Structures via Ligand-Free Pd-Catalyzed C-H Activation/[5 + 1] Cyclization Carbonylation.

An approach for the ligand-free Pd-catalyzed C-H activation/[5 + 1] cyclization carbonylation by employing readily available ClCF2COONa as a carbonyl source via difluorocarbene transfer and hydrolysis has been developed. The current protocol enables us to obtain a series of carbonylation cyclization product benzopyranone and phenanthridinone derivatives in up to 91% yield with excellent functional group compatibility. This protocol has the advantages of mild reaction conditions, wide applicable substrates, and simple and safe operation and provides a new method for the synthesis of complex lactam and lactone compounds.

Functional evaluation of non-oxidative glycolysis in Escherichia coli in the stationary phase under microaerobic conditions

In microbial bioproduction, CO2 emissions via pyruvate dehydrogenase in the Embden-Meyerhof pathway, which converts glucose to acetyl-CoA, is one of the challenges for enhancing carbon yield. The synthetic non-oxidative glycolysis (NOG) pathway transforms glucose into three acetyl-CoA molecules without CO2 emission, making it an attractive module for metabolic engineering. Because the NOG pathway generates no ATP and NADH, it is expected to use a resting cell reaction. Therefore, it is important to characterize the feasibility of the NOG pathway during stationary phase. Here, we experimentally evaluated the invivo metabolic flow of the NOG pathway in Escherichia coli. An engineered strain was constructed by introducing phosphoketolase from Bifidobacterium adolescentis into E.coli and by deleting competitive reactions. When the strain was cultured in magnesium-starved medium under microaerobic conditions, the carbon yield of acetate, an end-product of the NOG pathway, was six times higher than that of the control strain harboring an empty vector. Based on the mass balance constraints, the NOG flux was estimated to be between 2.89 and 4.64mmolg-1h-1, suggesting that the engineered cells can convert glucose through the NOG pathway with enough activity for bioconversion. Furthermore, to expand the application potential of NOG pathway-implemented strains, the theoretical maximum yields of various useful compounds were calculated using flux balance analysis. This suggests that the theoretical maximum yields of not only acetate but also lactam compounds can be increased by introducing the NOG pathway. This information will help in future applications of the NOG pathway.

Phosphazene Base-Catalyzed Intramolecular Hydroamidation of Alkenes with Amides.

A method for the synthesis of cyclic amides via phosphazene base-catalyzed intramolecular hydroamidation of amide alkenes was developed. The reaction using a catalytic amount of P4-base had a good functional group tolerance and a broad substrate scope and could also be used to synthesize lactam, cyclic urea, and oxazolidinone compounds. This catalytic system was expanded to a one-pot intramolecular hydroamidation and intermolecular hydroalkylation. Deuterium labeling and radical trapping experiments provided mechanistic insights into the catalytic cycle of the hydroamidation reaction.

Discovery and Optimization of Seven-Membered Lactam-Based Compounds to Phenocopy the Inhibition of the Aurora Kinase B.

We used mechanism-informed phenotypic screening to identify and optimize compounds that phenocopy the genetic depletion of the mitotic aurora kinase B (AURKB) kinase. After assaying nine aryl fused seven-membered lactam compounds, we identified a hit compound 6a that was subsequently optimized to five lead compounds with low nanomolar activity, represented by the lead compound 6v (19 nM). With excellent drug-like properties, these compounds reproduced the loss of function in phenotypes of AURKB and exhibited potent cytotoxic activities in various cancer cell lines. Collectively, these data support that seven-membered lactam-based analogs might be valuable for further development as a new type of antimitotic agents for the treatment of cancer.

Carboxylic acid reductases enable intramolecular lactamization reactions

As a versatile type of enzyme, carboxylic acid reductases (CAR) can not only reduce various carboxylic acids to aldehydes in cooperation with cofactors ATP and NADPH but also catalyze the synthesis of amides and esters in the absence of NADPH. Here, we report an intramolecular cyclization catalyzed by CAR only with the use of ATP to transform amino acids into diverse lactams, including γ-/δ-/ε-lactams and chiral derivatives thereof. The observed wide substrate scope and selectivity enable potential applications to be implemented. Our results demonstrate that CAR-catalyzed lactamization is a promising approach for the synthesis of chiral lactam compounds under mild conditions, thereby enriching the toolbox for the biosynthesis of lactams as a viable alternative to purely chemical procedures.

Dipole Moment and Anticancer Activity of Beta Lactams

This study investigates the correlation between in vitro anticancer activity and dipole moments of beta lactams by calculating the dipole moment with five different semiempirical methods (Austin model 1/Recife model 1/Parametric model number 3/Parametric model number 6/ Modified neglect of differential overlap). Dipole moment value is analyzed to identify a correlation of experimental anticancer activity of beta lactams. To the best of our knowledge, this is the first report on relationship between dipole moment and anticancer activities of beta lactams. Six beta lactam compounds are considered for this study. It is observed that the active compounds have a significantly higher dipole moment value (ranging from 5.12 to 4.3) compared to inactive compounds (ranging from 3.8 to 2.29). These data indicate that dipole moment might be a useful parameter for the estimation of the biological activity of beta lactams. This study also aims to determine the most prominent descriptor for cytotoxic activity of beta lactams to aid the development of more active anticancer agents.

Enantioselective total synthesis of (+)-rubrobramide, (+)-talaramide A, and (-)-berkeleyamide D by a skeletal diversification strategy.

A unified synthesis of (+)-rubrobramide, (+)-talaramide A, and (-)-berkeleyamide D was achieved from the vinylogous esters by a skeletal diversification strategy based on regioselective 5-exo or 6-endo cyclization. This report describes the first enantioselective total synthesis of (+)-rubrobramide and (+)-talaramide A. Additionally, synthetic spirocyclic lactam compounds, including (-)-berkeleyamide D, showed moderate inhibitory activity against amyloid-β aggregation for the potential treatment of Alzheimer's disease.

An Integrated Cofactor/Co-Product Recycling Cascade for the Biosynthesis of Nylon Monomers from Cycloalkylamines.

We report a highly atom-efficient integrated cofactor/co-product recycling cascade employing cycloalkylamines as multifaceted starting materials for the synthesis of nylon building blocks. Reactions using E. coli whole cells as well as purified enzymes produced excellent conversions ranging from >80 and 95 % into desired ω-amino acids, respectively with varying substrate concentrations. The applicability of this tandem biocatalytic cascade was demonstrated to produce the corresponding lactams by employing engineered biocatalysts. For instance, ϵ-caprolactam, a valuable polymer building block was synthesized with 75 % conversion from 10 mM cyclohexylamine by employing whole-cell biocatalysts. This cascade could be an alternative for bio-based production of ω-amino acids and corresponding lactam compounds.

An Integrated Cofactor/Co‐Product Recycling Cascade for the Biosynthesis of Nylon Monomers from Cycloalkylamines

AbstractWe report a highly atom‐efficient integrated cofactor/co‐product recycling cascade employing cycloalkylamines as multifaceted starting materials for the synthesis of nylon building blocks. Reactions using E. coli whole cells as well as purified enzymes produced excellent conversions ranging from >80 and 95 % into desired ω‐amino acids, respectively with varying substrate concentrations. The applicability of this tandem biocatalytic cascade was demonstrated to produce the corresponding lactams by employing engineered biocatalysts. For instance, ϵ‐caprolactam, a valuable polymer building block was synthesized with 75 % conversion from 10 mM cyclohexylamine by employing whole‐cell biocatalysts. This cascade could be an alternative for bio‐based production of ω‐amino acids and corresponding lactam compounds.

Study the Biological Activity for Shiff Base and Β–Lactam Compounds that Synthesis and Identification from Pyrimidine Derivatives

In This study We are synthesis and characterization of some Schiff base and β- lactam derivatives) by three steps. The First react 2-amino-4-Chloro-6-methyl pyrimidine with 4-amino acetophenone in an acid medium to get shiff base derivative(E)-4-(1-((4-Chloro-6-methyl pyridine-2-yl)imino)ethyl)aniline (1), the second step (1) react with (3,4-dimethoxybenzal dehyde,4-methyl benzaldehyde,4-dimethylamino benzaldehyde,4-bromo benzaldehyde,4–hydroxy benzaldehyde, 4-Nitro benzaldehyde) to get Schiff base derivatives (2-7), the last step (2-7) derivatives react with Chloro acetyl chloride to get –β-lactam derivatives.(8-13) All these compounds are characterization by Fourier Transform Infrared Spectroscopy (FTIR), (1 H-NMR),(13C- NMR). After that study, the biological activity for all these derivatives to word two kinds of bacteria study the Enzymatic and Cancer Cell.

A Novel, Domino Synthesis of Tricyclic Benzimidazole Derivatives Using Continuous Flow

A novel method for synthesis of tricyclic benzimidazole derivatives by using continuous flow reactor is reported. Disadvantages of the well-known batch methods have been avoided utilizing the flow chemistry technology. Beside the one pot reductive cyclization using H-Cube Pro®, the dehydration step was also optimized producing the desired lactam compounds. Then the acylation was optimized under microwave conditions and that reaction was also integrated into the flow system using an Asia heater module. This acylation dramatically reduced the reaction time under continuous-flow conditions, with a residence time of 30 min.

Jetting performance of two lactam compounds in reactive dye solution

Digital inkjet printing technology has great significance in textiles. In this paper, influences of two additives on the dye aggregation and jetting performance of reactive dye solutions are investigated, and the mechanism is analyzed. We explored the physical properties and jetting performance of reactive dye solutions with 2-pyrrolidone (PY) or N-methyl pyrrolidone (NMP) by testing UV–visible absorption spectrum, rheological properties, surface tension, and observing the droplet formation. The results showed that PY and NMP could inhibit the dye aggregation. Moreover, two lactam compounds decreased the surface tension and increased the viscosity of dye solutions by the interaction between lactam compounds and reactive dye. PY and NMP could reduce the generation of satellite droplets of dye solutions. In addition, 5% PY/Red 218 and 5% NMP/Red 218 solutions produced better color images on cotton fabrics.

A synthetic microbial biosensor for high-throughput screening of lactam biocatalysts

Biocatalytic cyclization is highly desirable for efficient synthesis of biologically derived chemical substances, such as the commodity chemicals ε-caprolactam and δ-valerolactam. To identify biocatalysts in lactam biosynthesis, we develop a caprolactam-detecting genetic enzyme screening system (CL-GESS). The Alcaligenes faecalis regulatory protein NitR is adopted for the highly specific detection of lactam compounds against lactam biosynthetic intermediates. We further systematically optimize the genetic components of the CL-GESS to enhance sensitivity, achieving 10-fold improvement. Using this highly sensitive GESS, we screen marine metagenomes and find an enzyme that cyclizes ω-amino fatty acids to lactam. Moreover, we determine the X-ray crystal structure and catalytic residues based on mutational analysis of the cyclase. The cyclase is also used as a helper enzyme to sense intracellular ω-amino fatty acids. We expect this simple and accurate biosensor to have wide-ranging applications in rapid screening of new lactam-synthesizing enzymes and metabolic engineering for lactam bio-production.

Fungal Lactamases: Their Occurrence and Function.

Fungi are absorptive feeders and thus must colonize and ramify through their substrate to survive. In so doing they are in competition, particularly in the soil, with myriad microbes. These microbes use xenobiotic compounds as offensive weapons to compete for nutrition, and fungi must be sufficiently resistant to these xenobiotics. One prominent mechanism of xenobiotic resistance is through production of corresponding degrading enzymes. As typical examples, bacterial β-lactamases are well known for their ability to degrade and consequently confer resistance to β-lactam antibiotics, a serious emerging problem in health care. We have identified many fungal genes that putatively encode proteins exhibiting a high degree of similarity to β-lactamases. However, fungal cell walls are structurally different from the bacterial peptidoglycan target of β-lactams. This raises the question, why do fungi have lactamases and what are their functions? Previously, we identified and characterized one Fusarium verticillioides lactamase encoding gene (FVEG_08291) that confers resistance to the benzoxazinoid phytoanticipins produced by maize, wheat, and rye. Since benzoxazinoids are γ-lactams with five-membered rings rather than the four-membered β-lactams, we refer to the predicted enzymes simply as lactamases, rather than β-lactamases. An overview of fungal genomes suggests a strong positive correlation between environmental niche complexity and the number of fungal lactamase encoding genes, with soil-borne fungi showing dramatic amplification of lactamase encoding genes compared to those fungi found in less biologically complex environments. Remarkably, Fusarium species frequently possess large (>40) numbers of these genes. We hypothesize that many fungal hydrolytic lactamases are responsible for the degradation of plant or microbial xenobiotic lactam compounds. Alignment of protein sequences revealed two conserved patterns resembling bacterial β-lactamases, specifically those possessing PFAM domains PF00753 or PF00144. Structural predictions of F. verticillioides lactamases also suggested similar catalytic mechanisms to those of their bacterial counterparts. Overall, we present the first in-depth analysis of lactamases in fungi, and discuss their potential relevance to fitness and resistance to antimicrobials in the environment.

Calcium Sensitizers Isolated from the Edible Pine Mushroom, Tricholoma matsutake (S. Ito & Imai) Sing

Three lactam compounds were isolated from the fruiting body of Tricholoma matsutake (S. Ito & Imai) Sing., an edible mushroom, and their structures were identified as cyclo-S-proline-R-leucine (1), hexahydro-2H-azepin-2-one (2), and butyl 5-oxo-2-pyrrolidine carboxylate (3) by chemical, physicochemical, and spectral evidence. In in vitro screening tests, compounds 1 and 2 acted as calcium sensitizers in ventricular cells from rat. Further studies on compounds 1 and 2 in ex vivo isolated right atria showed positive inotropic effects without disturbing the spontaneous beating rate. The inotropic effect of compounds 1 and 2 could be greatly abolished by pretreating the myocardium in Ca(2+)-free solution. These findings indicate that compounds 1 and 2 can significantly increase the calcium ion concentration ([Ca2+]i) in myocytes, which is greatly dependent on the influx of extracellular Ca2+.

DETECTION OF METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS (MRSA) FROM ANIMAL AND HUMAN ORIGIN IN BANGLADESH BY POLYMERASE CHAIN REACTION

Methicillin-resistant Staphylococcus aureus (MRSA) is defined by the presence of the mecA gene, which is considered to have been transferred horizontally from unknown bacterial species to S. aureus. The mecA gene which encodes an additional ?-lactam-resistant penicillin-binding protein (PBP), termed PBP-2a (PBP-2’) with reduced binding affinity for ?-lactam compounds. We investigated distribution of the mecA gene in a total of 94 clinical strains of S. aureus isolated from both man and animal admitted in Bangladeshi medical hospital as well as Veterinary clinic. The mecA gene was detected by PCR in 25% of human clinical isolates of S. aureus, whereas not a single mecA gene was detected in animal isolates of S. aureus.DOI: http://dx.doi.org/10.3329/bjvm.v9i2.13472

Efficient Regio- and Stereoselective Synthesis of 5-Alkyl(aryl)idene- and 5-[Iodoalkyl(aryl)idene]-1H-pyrrol-2(5H)-ones via Electrophilic Cyclization

A variety of substituted 5-alkyl(aryl)idene- and 5-[iodoalkyl(aryl)idene]-1H-pyrrol-2(5H)-ones were readily prepared with good yields under very mild reaction conditions by the iodocyclization of (2Z,4E)-dienamides and (Z)-alk-2-en-4-ynamides with iodine monochloride. 3-Ylidene-isoindolin-1-ones were also synthesized in moderate to good yields under the same conditions. The methodology proceeded with total regioselectivity in all cases and was applied to the synthesis of new unsaturated lactam compounds.

The Screening, Characterization, and Use of ω-Laurolactam Hydrolase: A New Enzymatic Synthesis of 12-Aminolauric Acid

Several omega-laurolactam degrading microorganisms were isolated from soil samples. These strains were capable of growing in a medium containing omega-laurolactam as sole source of carbon and nitrogen. Among them, five strains (T7, T31, U124, U224, and U238) were identified as Cupriavidus sp. T7, Acidovorax sp. T31, Cupriavidus sp. U124, Rhodococcus sp. U224, and Sphingomonas sp. U238, respectively. The omega-laurolactam hydrolyzing enzyme from Rhodococcus sp. U224 was purified to homogeneity, and its enzymatic properties were characterized. The enzyme acts on omega-octalactam and omega-laurolactam, but other lactam compounds, amides and amino acid amides, cannot be substrates. The enzyme gene was cloned, and the deduced amino acid sequence showed high homology with 6-aminohexanoate-cyclic-dimer hydrolase (EC 3.5.2.12) from Arthrobacter sp. KI72 and Pseudomonas sp. NK87. Enzymatic synthesis of 12-aminolauric acid was performed using partially purified omega-laurolactam hydrolase from Rhodococcus sp. U224.

Isolation and characterization of new lactam compounds that inhibit lung and colon cancer cells from adlay (Coix lachryma-jobi L. var. ma-yuen Stapf) bran

Five active compounds that inhibit cancer cells were isolated from adlay bran (Coix lachryma-jobi L. var. ma-yuen Stapf), and their structures and activities in vitro were characterized. The ethyl acetate-soluble fraction of methanol extracts of adlay bran (ABM-EtOAc) exhibited a stronger anti-proliferative effect on human lung cancer cell A549, human colorectal carcinoma cell HT-29, and COLO 205 than other fractions by MTT (3-4,5-dimethylthiazol-2-yl-2,5-diphenyl-tetrazolium bromide) assay. Assay-guided isolation gave five lactams including three that were previously undocumented; coixspirolactam A (1), coixspirolactam B (2), and coixspirolactam C (3); one isolated from the natural plant for the first time, coixlactam (4); and one known compound, methyl dioxindole-3-acetate (5). Pure active compounds were identified by spectral analysis including IR, 1H and 13C NMR, UV–vis, MS and 2D NMR techniques. All the compounds were tested for their anti-proliferative effect on A549, HT-29 and COLO 205 cells. These compounds showed anti-cancer activities with IC50 values between 28.6 and 72.6μg/mL.

Future chemotherapy, with emphasis on bacterial murein

The purpose of this article is: first, to suggest strategies to look for antibiotics that should have a long useful life, even if heavily used; second, to focus on the structure and metabolism of bacterial walls as a still rich area for study to find useful antibiotics; and third, to present the bacterial wall biology from an historical perspective. We need to know: 1. Why has the bacterial sacculus been so useful to bacteria? (Koch, 1981, 1983, 1991, 1994, 1995, 1998, 2000a,b, 2001, 2002, 2003, 2005; Koch & Woeste, 1992; Koch & Silver, 2005) [Except for Ghuysen & Hakenbeck (1994), which is the most current book on the bacterial cell wall, I have cited only references to my earlier reviews, but they will lead to the earlier literature.] This topic became relevant at the time of the branching of life on this planet to give the domains of Bacteria and Archaea / Eukarya three billion years ago. The former organisms had the protective wall and the later organisms devised ways to combat bacteria. We add, therefore: 2. Why and how did the bacterial wall become the first important target of natural antibiotics? (Koch, 1981, 1983, 1991, 1994, 1995, 1998, 2000a,b, 2001, 2002, 2003, 2005; Koch & Woeste, 1992; Koch & Silver, 2005) 3. Why were lactam compounds so successful at killing bacteria? (See Koch, 2000) 4. How did β-lactamases develop? (Koch, 2000, 2003, 2005) These questions are pertinent to microbiologists, medical specialists and the pharmaceutical industry, and have essentially been answered. Because the genes for lactamases are present in the world microbial community, novel strategies are necessary to …