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Angewandte Chemie (International Ed. in... Apr 2020An azanorbornadiene bromovinyl sulfone reagent for cysteine-selective bioconjugation has been developed. Subsequent reaction with dipyridyl tetrazine leads to bond...
An azanorbornadiene bromovinyl sulfone reagent for cysteine-selective bioconjugation has been developed. Subsequent reaction with dipyridyl tetrazine leads to bond cleavage and formation of a pyrrole-linked conjugate. The latter involves ligation of the tetrazine to the azanorbornadiene-tagged protein through inverse electron demand Diels-Alder cycloaddition with subsequent double retro-Diels-Alder reactions to form a stable pyrrole linkage. The sequence of site-selective bioconjugation followed by bioorthogonal bond cleavage was efficiently employed for the labelling of three different proteins. This method benefits from easy preparation of these reagents, selectivity for cysteine, and stability after reaction with a commercial tetrazine, which has potential for the routine preparation of protein conjugates for chemical biology studies.
Topics: Aza Compounds; Cycloaddition Reaction; Cysteine; Norbornanes; Pyrroles
PubMed: 31981460
DOI: 10.1002/anie.201914529 -
Biochemical Pharmacology Oct 2017Formyl peptide receptors (FPRs) are expressed on a variety of leukocytes and play important roles in inflammation. Thus, FPR antagonists may represent novel therapeutics...
Formyl peptide receptors (FPRs) are expressed on a variety of leukocytes and play important roles in inflammation. Thus, FPR antagonists may represent novel therapeutics for modulating innate immunity and treating inflammatory diseases. Previously, 1H-pyrrol-2(5H)-ones were reported to be potent and competitive FPR1 antagonists. In the present studies, 42 additional 1H-pyrrol-2(5H)-one analogs were evaluated for FPR1 antagonist activity. We identified a number of novel competitive FPR1 antagonists that inhibited N-formylmethionyl-leucyl-phenylalanine (fMLF)-induced intracellular Ca mobilization in FPR1-transfected HL60 cells and effectively competed with WKYMVm-FITC for binding to FPR1 in FPR1-transfected RBL cells. The most active pyrroles inhibited human neutrophil Ca flux, chemotaxis, and adhesion to human epithelial cells, with the most potent being compounds 14 (4-benzoyl-1-hexyl-3-hydroxy-5-(4-hydroxy-3-methoxyphenyl)-2,5-dihydro-1H-pyrrol-2-one) and 17 (4-benzoyl-5-(2,5-dimethoxyphenyl)-3-hydroxy-1-(2-methoxyethyl)-2,5-dihydro-1H-pyrrol-2-one). In addition, these FPR1 antagonists inhibited fMLF-induced phosphorylation of extracellular signal-regulated kinases (ERK1/2) in FPR1-RBL cells, differentiated HL-60 cells, and human neutrophils. Most of the antagonists were specific for FPR1 and did not inhibit WKYMVM/WKYMVm-induced intracellular Ca mobilization in FPR2-HL60 cells, FPR3-HL60 cells, or interleukin 8-induced Ca flux in human neutrophils. Moreover, molecular modeling showed that the active pyrroles had a significantly higher degree of similarity with the FPR1 antagonist pharmacophore template as compared to inactive analogs. Thus, the 4-aroyl-3-hydroxy-5-phenyl-1H-pyrrol-2(5H)-one scaffold represents an important backbone for the development of novel FPR1 antagonists and could provide important clues for understanding the molecular structural requirements of FPR1 antagonists.
Topics: Anti-Inflammatory Agents; Binding, Competitive; Calcium; Cell Adhesion; Cell Culture Techniques; Chemotaxis, Leukocyte; Dose-Response Relationship, Drug; HL-60 Cells; Humans; Molecular Docking Simulation; Molecular Structure; Neutrophils; Pyrroles; Receptors, Formyl Peptide; Structure-Activity Relationship; Transfection
PubMed: 28690139
DOI: 10.1016/j.bcp.2017.07.004 -
The Journal of Organic Chemistry Jun 2022The present work focuses on a theoretical investigation of mechanistic features, chemoselectivity, regioselectivity, and effect of substituents in the gold-catalyzed...
The present work focuses on a theoretical investigation of mechanistic features, chemoselectivity, regioselectivity, and effect of substituents in the gold-catalyzed reactions of alkynyl thioethers and isoxazoles. The DFT calculations reveal that the nucleophilic attack of isoxazole to a βposition of catalyst-bound ynamide forms a vinyl intermediate. This undergoes cleavage of the N-O isoxazole bond and isomerizes to form an α-imino -sulfenyl gold carbene complex with stabilization of the Au-S interaction. For 3,5-dimethylisoxazole, the reaction follows a formal [3 + 2] cycloaddition pathway and a 1,3-H migration to give the pyrrole products. Replacement of 3,5-dimethylisoxazole by 3,5-dimethyl-4-phenylisoxazole leads to the formation of deacylative annulation products and desulfenylated 3-acylated pyrroles. Reactions with 4-methyl-3,5-diphenylisoxazoles induce the formation of -acylated pyrroles and desulfenylated 3-acylated pyrroles. For the minor pathway, the α-addition and 1,2-S migration result in sulfur-substituted β-keto enamide derivatives. In addition, the unique features of regio- and chemoselectivity were rationalized by the distortion and interaction analysis. Apart from fully rationalizing the experimental results, the theoretical DFT data give an important support for comprehending related types of reaction mechanisms.
Topics: Catalysis; Gold; Isoxazoles; Pyrroles; Rationalization; Sulfides
PubMed: 35579210
DOI: 10.1021/acs.joc.2c00407 -
Discovery of sulfadrug-pyrrole conjugates as carbonic anhydrase and acetylcholinesterase inhibitors.Archiv Der Pharmazie Jan 2022Human carbonic anhydrase (hCA) isoenzymes are zinc ion-containing, widespread metalloenzymes and they classically play a role in pH homeostasis maintenance. CA... (Comparative Study)
Comparative Study
Human carbonic anhydrase (hCA) isoenzymes are zinc ion-containing, widespread metalloenzymes and they classically play a role in pH homeostasis maintenance. CA inhibitors suppress the CA activity and their usage has been clinically established as antiglaucoma agents, antiepileptics, diuretics, and in some other disorders. Alzheimer's disease (AD) is a slowly progressive neurodegenerative disorder and a fatal disease of the brain. An advanced method to cure AD includes the strategy to design acetylcholinesterase (AChE) inhibitors. A novel series of pyrrole-3-one derivatives containing sulfa drugs (5a-i) were determined to be highly potent inhibitors for AChE and hCA I and hCA II (inhibitory constant [K ] values are in the range of 6.50 ± 1.02-37.46 ± 4.12 nM, 1.20 ± 0.19-44.21 ± 1.09 nM, and 8.93 ± 1.58-46.86 ± 8.41 nM for AChE, hCA I, and hCA II, respectively). The designed compounds often show a more effective inhibition than the chemicals used as the standard. Among these compounds, 5f was the most effective compound against hCA I, and compound 5e was the most effective compound against hCA II. It was determined that compound 5c was the most effective inhibitor for AChE.
Topics: Carbonic Anhydrase I; Carbonic Anhydrase II; Carbonic Anhydrase Inhibitors; Cholinesterase Inhibitors; Humans; Isoenzymes; Pyrroles; Structure-Activity Relationship; Sulfonamides
PubMed: 34609760
DOI: 10.1002/ardp.202100242 -
Molecules (Basel, Switzerland) Nov 2021The 3-hydroxy-1,5-dihydro-2-pyrrol-2-one motif is a valuable scaffold in drug discovery. The replacement of the 3-oxy fragment in...
The 3-hydroxy-1,5-dihydro-2-pyrrol-2-one motif is a valuable scaffold in drug discovery. The replacement of the 3-oxy fragment in 3-hydroxy-1,5-dihydro-2-pyrrol-2-ones-based compounds with a 3-amino one (3-amino analogs of 3-hydroxy-1,5-dihydro-2-pyrrol-2-ones, 3-amino-1,5-dihydro-2-pyrrol-2-ones) can play a crucial role in their biological effect. Thus, approaches to 3-amino-1,5-dihydro-2-pyrrol-2-ones are of significant interest. We developed an approach to 5-spiro-substituted 3-amino-1,5-dihydro-2-pyrrol-2-ones that could not be obtained using previously reported approaches (reactions of 3-hydroxy-1,5-dihydro-2-pyrrol-2-ones with amines). The developed approach is based on the thermal decomposition of 1,3-disubstituted urea derivatives of 5-spiro-substituted 3-hydroxy-1,5-dihydro-2-pyrrol-2-ones, which were prepared their reaction with carbodiimides.
Topics: Amination; Amines; Carbodiimides; Drug Discovery; Molecular Structure; Pyrroles
PubMed: 34885757
DOI: 10.3390/molecules26237179 -
International Archives of Occupational... Aug 2019Urinary excretion of 2,5-hexanedione is currently used to estimate the exposure levels of hexane occurring to an individual during the previous work shift. However,...
OBJECTIVES
Urinary excretion of 2,5-hexanedione is currently used to estimate the exposure levels of hexane occurring to an individual during the previous work shift. However, because hexane exposures and urinary 2,5-hexanedione levels can vary considerably from day to day, and subchronic to chronic exposures to hexane are required to produce neuropathy, this biomarker may not accurately reflect the risk of an individual for developing hexane neuropathy. This investigation examines the potential of hexane-derived pyrrole adducts produced on globin and plasma proteins as markers for integrating cumulative exposures. Because the pyrrole markers incorporate bioactivation of hexane to 2,5-hexandione and the initial step of protein adduction involved in hexane-induced neuropathy, they potentially can serve as biomarkers of effect through reflecting pathogenetic events within the nervous system. Additionally, pyrrole formation is an irreversible reaction suggesting that hexane-derived protein pyrroles can be used to assess cumulative exposures to provide a better characterization of individual susceptibilities.
METHODS
To examine the utility of the proposed markers, blood samples were obtained from eleven workers who used hexane for granulating metal powders in a slurry to produce metal machining die tools and four non-exposed volunteers. Globin and plasma were isolated, and the proteins were digested using pepsin, reacted with Ehrlich's reagent and the level of pyrrole adducts were determined by absorbance at 530 nm. To determine the dose-response curve and dynamic range of the assay, erythrocytes were incubated with a range of 2,5-hexanedione concentrations and the net absorbance at 530 nm of isolated globin was measured.
RESULTS
Pyrrole was detected in both the globin and plasma samples of the workers exposed to hexane and the levels of pyrroles in plasma were positively correlated with the levels of pyrroles in globin for most of the workers.
CONCLUSIONS
This investigation demonstrates that detectable levels of hexane-derived protein pyrrole adducts are produced on peripheral proteins following occupational exposures to hexane and supports the utility of measuring pyrroles for integrating cumulative exposures to hexane.
Topics: Biomarkers; Globins; Hexanes; Humans; Occupational Exposure; Plasma; Pyrroles
PubMed: 30955093
DOI: 10.1007/s00420-019-01430-7 -
Anti-cancer Agents in Medicinal... 2022Heterocyclic compounds are that type of substances that are deeply intertwined with biological processes. Heterocycles are found in about 90% of commercially available... (Review)
Review
Heterocyclic compounds are that type of substances that are deeply intertwined with biological processes. Heterocycles are found in about 90% of commercially available medicines. In medicinal chemistry, finding new synthetic molecules with drug-like characteristics is a regular problem, which triggered the development of pharmacological molecules, the majority of which are based on N-heterocyclic motifs. Among the heterocycles, the pyrrole scaffold is the most commonly found heterocycle in both natural and synthetic bioactive compounds. Pyrrole has a fivemembered heterocyclic ring with a plethora of pharmacophores, resulting in a library of different lead compounds. Pyrrole derivatives are physiologically active heterocyclic compounds that can be used as scaffolds for antibacterial, antiviral, anticancer, antitubercular, anti-inflammatory, and as enzyme inhibitors. On account of their extensive pharmacological profile, pyrrole and its various synthetic derivatives have drawn much attention from researchers to explore it for the benefit of humankind. This review presents an overview of recent developments in the pyrrole derivatives against multiple therapeutic targets.
Topics: Anti-Bacterial Agents; Antiviral Agents; Enzyme Inhibitors; Heterocyclic Compounds; Humans; Pyrroles
PubMed: 35702764
DOI: 10.2174/1871520622666220613140607 -
Mini Reviews in Medicinal Chemistry 2018Pyrrole-2-aminoimidazole compounds are found in marine organisms, mainly as secondary metabolites in various marine sponges. Studies of natural pyrrole-2-aminoimidazole... (Review)
Review
Pyrrole-2-aminoimidazole compounds are found in marine organisms, mainly as secondary metabolites in various marine sponges. Studies of natural pyrrole-2-aminoimidazole compounds showed that they possess different pharmacological properties, such as antimicrobial, antibiofilm, immunosuppressive and anticancer activities. Many analogs of the natural compounds have been synthesized to improve their biological activities. This review focuses on the antibacterial and antibiofilm potentials of natural pyrrole-2-aminoimidazoles and their synthetic analogs and derivatives, as well as on the structure-activity relationships of the most promising compounds. Known molecular targets of these compounds in bacterial cells are also described here, as is the synergistic activity of the pyrrole- 2-aminoimidazoles and conventional antibiotics.
Topics: Alkaloids; Anti-Bacterial Agents; Aquatic Organisms; Biofilms; Imidazoles; Microbial Sensitivity Tests; Pyrroles; Seawater; Structure-Activity Relationship
PubMed: 27145848
DOI: 10.2174/1389557516666160505120157 -
Chemistry & Biodiversity Oct 2021The present study illustrates the design and synthesis of new series of 3-trifluoromethylpyrazole tethered chalcone-pyrrole and pyrazoline-pyrrole derivatives. All...
The present study illustrates the design and synthesis of new series of 3-trifluoromethylpyrazole tethered chalcone-pyrrole and pyrazoline-pyrrole derivatives. All compounds were further screened for in vitro cytostatic activities on full NCI 60 cancer cell lines at National Cancer Institute, USA. Compounds (2E)-3-(1H-pyrrol-2-yl)-1-{4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}prop-2-en-1-one (5a) and (2E)-1-{3-methyl-4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-3-(1H-pyrrol-2-yl)prop-2-en-1-one (5c) displayed significant antiproliferative activity (Growth Percentage: -77.10 and -92.13, respectively at 10 μM concentration) against the UO-31 cell lines from renal cancer and were further selected for assay at 10-fold dilutions of five different concentrations (10 to 10 M). Both compounds 5a and 5c exhibited promising antiproliferative activity (GI : 1.36 to 0.27 μM) against leukemia cancer cell lines HL-60 and RPMI-8226, colon cancer cell lines KM-12; breast cancer cell lines BT-549. Moreover, both compounds 5a and 5c were found to be non-cytotoxic (LC >100) against HL-60, RPMI-8226, and KM-12 cell lines. Remarkably, GI values of compounds 5a and 5c were identified as more promising than sunitinib against most cancer cell lines. In silico study of compounds 5a and 5c exemplified the desired ADME properties for drug-likeness as well as tighter interactions with VEGFR-2. Hence, compounds 5a and 5c would be good cytotoxic agents after further clinical study.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Chalcone; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Pyrazoles; Pyrroles; Structure-Activity Relationship
PubMed: 34409724
DOI: 10.1002/cbdv.202100504 -
Chembiochem : a European Journal of... Apr 2019A model cancer cell line was used to initiate polymerisation of pyrrole to form the conducting material polypyrrole. The polymerisation was shown to occur through the...
A model cancer cell line was used to initiate polymerisation of pyrrole to form the conducting material polypyrrole. The polymerisation was shown to occur through the action of cytosolic exudates rather than that of the membrane redox sites that normally control the oxidation state of iron as ferricyanide or ferrocyanide. The data demonstrate for the first time that mammalian cells can be used to initiate synthesis of conducting polymers and suggest a possible route to detection of cell damage and/or transcellular processes through in situ and amplifiable signal generation.
Topics: Animals; Humans; K562 Cells; Polymerization; Pyrroles
PubMed: 30570811
DOI: 10.1002/cbic.201800630