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465 results on '"Schepetkin, Igor A."'

102. Synthesis, HPLC enantioresolution and X-ray analysis of a new series of C5-methyl pyridazines as N-formyl peptide receptor (FPR) agonists

Author

Cilibrizzi, Agostino, Crocetti, Letizia, Giovannoni, Maria Paola, Graziano, Alessia, Vergelli, Claudia, Bartolucci, Gianluca, Soldani, Giacomo, Quinn, Mark T., Schepetkin, Igor A., and Faggi, Cristina

Subjects
Pyridazines, Humans, HL-60 Cells, Stereoisomerism, Chiral stationary phase, FPRs, Chemistry Techniques, Synthetic, sense organs, Crystallography, X-Ray, Receptors, Formyl Peptide, Article, Chromatography, High Pressure Liquid
Abstract

The synthesis of three racemates and the corresponding non chiral analogues of a C5-methyl pyridazine series is described here, as well as the isolation of pure enantiomers and their absolute configuration assignment. In order to obtain optically active compounds, direct chromatographic methods of separation by HPLC-UV were investigated using four chiral stationary phases (CSPs: Lux Amylose-2®, Lux Cellulose-1®, Lux Cellulose-2® and Lux Cellulose-3®). The best resolution was achieved using amylose tris(5-chloro-2-methylphenylcarbamate) (Lux Amylose-2®), and single enantiomers were isolated on a semipreparative scale with high enantiomeric excess, suitable for biological assays. The absolute configuration of optically active compounds was unequivocally established by X-ray crystallographic analysis and comparative chiral HPLC-UV profile. All compounds of the series were tested for formyl peptide receptor (FPR) agonist activity, and four were found to be active, with EC50 values in the micromolar range.

Published
2013

103. Cinnoline derivatives as human neutrophil elastase inhibitors

Author

Giovannoni, Maria Paola, primary, Schepetkin, Igor A., additional, Crocetti, Letizia, additional, Ciciani, Giovanna, additional, Cilibrizzi, Agostino, additional, Guerrini, Gabriella, additional, Khlebnikov, Andrei I., additional, Quinn, Mark T., additional, and Vergelli, Claudia, additional

Published
2015
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105. Complement-fixing Activity of Fulvic Acid from Shilajit and Other Natural Sources

Author

Schepetkin, Igor A., Xie, Gang, Jutila, Mark A., and Quinn, Mark T.

Subjects
Erythrocytes, Sheep, Plant Extracts, Complement Fixation Tests, Chromatography, Gel, Linear Models, Animals, Benzopyrans, Medicine, Traditional, Galactans, Article, Humic Substances
Abstract

Shilajit has been used traditionally in folk medicine for the treatment of a variety of disorders, including syndromes involving excessive complement activation. Extracts of Shilajit contain significant amounts of fulvic acid (FA), and it has been suggested that FA is responsible for many therapeutic properties of Shilajit. However, little is known regarding the physical and chemical properties of Shilajit extracts, and nothing is known about their effects on the complement system. To address this issue, extracts of commercial Shilajit were fractionated using anion exchange and size-exclusion chromatography. One neutral (S-I) and two acidic (S-II and S-III) fractions were isolated, characterized and compared with standardized FA samples. The most abundant fraction (S-II) was further fractionated into three sub-fractions (S-II-1 to S-II-3). The van Krevelen diagram showed that the Shilajit fractions are the products of polysaccharide degradation, and all fractions, except S-II-3, contained type II arabinogalactan. All Shilajit fractions exhibited dose-dependent complement-fixing activity in vitro with high potency. Furthermore, a strong correlation was found between the complement-fixing activity and carboxylic group content in the Shilajit fractions and other FA sources. These data provide a molecular basis to explain at least part of the beneficial therapeutic properties of Shilajit and other humic extracts.

Published
2009

106. Isoxazol-5(2 H )-one: a new scaffold for potent human neutrophil elastase (HNE) inhibitors.

Author

Vergelli, Claudia, Schepetkin, Igor A., Crocetti, Letizia, Iacovone, Antonella, Giovannoni, Maria Paola, Guerrini, Gabriella, Khlebnikov, Andrei I., Ciattini, Samuele, Ciciani, Giovanna, and Quinn, Mark T.

Subjects
*NUCLEOPHILIC reactions, *SERINE proteinases, *EXTRACELLULAR matrix proteins, *OBSTRUCTIVE lung disease treatment, *BRONCHIECTASIS, *PHYSIOLOGY, *DIAGNOSIS
Abstract

Human neutrophil elastase (HNE) is an important target for the development of novel and selective inhibitors to treat inflammatory diseases, especially pulmonary pathologies. Here, we report the synthesis, structure–activity relationship analysis, and biological evaluation of a new series of HNE inhibitors with an isoxazol-5(2H)-one scaffold. The most potent compound (2o) had a good balance between HNE inhibitory activity (IC50value =20 nM) and chemical stability in aqueous buffer (t1/2=8.9 h). Analysis of reaction kinetics revealed that the most potent isoxazolone derivatives were reversible competitive inhibitors of HNE. Furthermore, since compounds2oand2scontain two carbonyl groups (2-N-CO and 5-CO) as possible points of attack for Ser195, the amino acid of the active site responsible for the nucleophilic attack, docking studies allowed us to clarify the different roles played by these groups. [ABSTRACT FROM PUBLISHER]

Published
2017
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110. Synthesis, HPLC Enantioresolution, and X-ray Analysis of a New Series of C5-methyl Pyridazines as N -Formyl Peptide Receptor (FPR) Agonists

Author

Cilibrizzi, Agostino, primary, Crocetti, Letizia, additional, Paola Giovannoni, Maria, additional, Graziano, Alessia, additional, Vergelli, Claudia, additional, Bartolucci, Gianluca, additional, Soldani, Giacomo, additional, Quinn, Mark T., additional, Schepetkin, Igor A., additional, and Faggi, Cristina, additional

Published
2013
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116. Cinnoline derivatives as human neutrophil elastase inhibitors.

Author

Giovannoni, Maria Paola, Schepetkin, Igor A., Crocetti, Letizia, Ciciani, Giovanna, Cilibrizzi, Agostino, Guerrini, Gabriella, Khlebnikov, Andrei I., Quinn, Mark T., and Vergelli, Claudia

Subjects
*HETEROCYCLIC compounds, *LEUCOCYTE elastase, *ENZYME inhibitors, *INFLAMMATION treatment, *AQUEOUS solutions, *MOLECULAR docking, *THERAPEUTICS
Abstract

Compounds that can effectively inhibit the proteolytic activity of human neutrophil elastase (HNE) represent promising therapeutics for treatment of inflammatory diseases. We present here the synthesis, structure–activity relationship analysis, and biological evaluation of a new series of HNE inhibitors with a cinnoline scaffold. These compounds exhibited HNE inhibitory activity but had lower potency compared toN-benzoylindazoles previously reported by us. On the other hand, they exhibited increased stability in aqueous solution. The most potent compound,18a, had a good balance between HNE inhibitory activity (IC50value = 56 nM) and chemical stability (t1/2 = 114 min). Analysis of reaction kinetics revealed that these cinnoline derivatives were reversible competitive inhibitors of HNE. Furthermore, molecular docking studies of the active products into the HNE binding site revealed two types of HNE inhibitors: molecules with cinnolin-4(1H)-one scaffold, which were attacked by the HNE Ser195 hydroxyl group at the amido moiety, and cinnoline derivatives containing an ester function at C-4, which is the point of attack of Ser195. [ABSTRACT FROM AUTHOR]

Published
2016
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121. Chemical composition and phagocyte immunomodulatory activity of Ferula iliensisessential oils

Author

Oüzek, Gulmira, Schepetkin, Igor A., Utegenova, Gulzhakhan A., Kirpotina, Liliya N., Andrei, Spencer R., Oüzek, Temel, Baser, Kemal Huüsnuü Can, Abidkulova, Karime T., Kushnarenko, Svetlana V., Khlebnikov, Andrei I., Damron, Derek S., and Quinn, Mark T.

Abstract

Activation of neutrophils by Ferula iliensisessential oils enriched in (E/Z)-propenyl sec-butyl disulfides is mediated by activation of transient receptor potential V1 channels. Essential oil extracts from Ferula iliensishave been used traditionally in Kazakhstan for treatment of inflammation and other illnesses. Because little is known about the biologic activity of these essential oils that contributes to their therapeutic properties, we analyzed their chemical composition and evaluated their phagocyte immunomodulatory activity. The main components of the extracted essential oils were (E)-propenyl sec-butyl disulfide (15.7–39.4%) and (Z)-propenyl sec-butyl disulfide (23.4–45.0%). Ferulaessential oils stimulated [Ca2+]imobilization in human neutrophils and activated ROS production in human neutrophils and murine bone marrow phagocytes. Activation of human neutrophil [Ca2+]iflux by Ferulaessential oils was dose-dependently inhibited by capsazepine, a TRPV1 channel antagonist, indicating that TRPV1 channels mediate this response. Furthermore, Ferulaessential oils stimulated Ca2+influx in TRPV1 channel–transfected HEK293 cells and desensitized the capsaicin-induced response in these cells. Additional molecular modeling with known TRPV1 channel agonists suggested that the active component is likely to be (Z)-propenyl sec-butyl disulfide. Our results provide a cellular and molecular basis to explain at least part of the beneficial therapeutic properties of FEOs.

Published
2017
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134. 6-Methyl-2,4-Disubstituted Pyridazin-3(2H)-ones: A Novel Class of Small-Molecule Agonists for Formyl Peptide Receptors

Author

Cilibrizzi, Agostino, primary, Quinn, Mark T., additional, Kirpotina, Liliya N., additional, Schepetkin, Igor A., additional, Holderness, Jeff, additional, Ye, Richard D., additional, Rabiet, Marie-Josephe, additional, Biancalani, Claudio, additional, Cesari, Nicoletta, additional, Graziano, Alessia, additional, Vergelli, Claudia, additional, Pieretti, Stefano, additional, Dal Piaz, Vittorio, additional, and Giovannoni, Maria Paola, additional

Published
2009
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143. Novel 3-(1H-indol-3-yl)-2-[3-(4-methoxyphenyl)ureido]propanamides as selective agonists of human formyl-peptide receptor 2.

Author

Lacivita, Enza, Schepetkin, Igor A., Stama, Madia L., Kirpotina, Liliya N., Colabufo, Nicola A., Perrone, Roberto, Khlebnikov, Andrei I., Quinn, Mark T., and Leopoldo, Marcello

Subjects
*INDOLE derivatives, *AMIDE synthesis, *FORMYL peptide receptors, *CHIRAL recognition, *NEUTROPHILS, *INFLAMMATION
Abstract

N -Formyl peptide receptors (FPRs) are G protein-coupled receptors (GPCRs) that play critical roles in inflammatory reactions, and FPR-specific interactions can possibly be used to facilitate the resolution of pathological inflammatory reactions. We here report the synthesis and biological evaluation of six pairs of chiral ureidopropanamido derivatives as potent and selective formyl peptide receptor-2 (FPR2) agonists that were designed starting from our lead agonist ( S )-3-(1 H -indol-3-yl)-2-[3-(4-methoxyphenyl)ureido]- N -[[1-(5-methoxy-2-pyridinyl)cyclohexyl]methyl]propanamide (( S )- 9a ). The new compounds were obtained in overall yields considerably higher than ( S )- 9a . Several of the new compounds showed agonist properties comparable to that of ( S )- 9a along with higher selectivity over FPR1. Molecular modeling was used to define chiral recognition by FPR2. In vitro metabolic stability of selected compounds was also assessed to obtain preliminary insight on drug-like properties of this class of compounds. [ABSTRACT FROM AUTHOR]

Published
2015
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146. Neutrophil Isolation From Nonhuman Species.

Author

Walker, John M., DeLeo, Frank R., Bokoch, Gary M., Siemsen, Daniel W., Schepetkin, Igor A., Kirpotina, Liliya N., Lei, Benfang, and Quinn, Mark T.

Abstract

Advances in the understanding of neutrophil biochemistry require the development of effective procedures for isolating purified neutrophil populations. Although methods for human neutrophil isolation are now standard, similar procedures for isolating neutrophils from many of the nonhuman species used to model human diseases are not as well developed. Because neutrophils are reactive cells, the method of isolation is extremely important to avoid isolation technique-induced alterations in cell function. We present methods here for reproducibly isolating highly-purified neutrophils from large (cow, horse, sheep) and small (mouse, rabbit) animal models and describe optimized details for obtaining the highest cell purity, yield, and viability. We also describe methods to verify phagocytic capacity in the purified cell populations using a flow cytometry-based phagocytosis assay. [ABSTRACT FROM AUTHOR]

Published
2007
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