2-Oxoesters: A Novel Class of Potent and Selective Inhibitors of Cytosolic Group IVA Phospholipase A2

Abstract Cytosolic phospholipase A2 (GIVA cPLA2) is the only PLA2 that exhibits a marked preference for hydrolysis of arachidonic acid containing phospholipid substrates releasing free arachidonic acid and lysophospholipids and giving rise to the generation of diverse lipid mediators involved in inf...

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Autores principales:	Maroula G. Kokotou, Gerasimia Galiatsatou, Victoria Magrioti, Giorgos Koutoulogenis, Efrosini Barbayianni, Dimitris Limnios, Varnavas D. Mouchlis, Banita Satpathy, Aaron Navratil, Edward A. Dennis, George Kokotos
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0316803c50ec492b8ba589202502cf1b
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spelling	oai:doaj.org-article:0316803c50ec492b8ba589202502cf1b2021-12-02T12:30:17Z2-Oxoesters: A Novel Class of Potent and Selective Inhibitors of Cytosolic Group IVA Phospholipase A210.1038/s41598-017-07330-52045-2322https://doaj.org/article/0316803c50ec492b8ba589202502cf1b2017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-07330-5https://doaj.org/toc/2045-2322Abstract Cytosolic phospholipase A2 (GIVA cPLA2) is the only PLA2 that exhibits a marked preference for hydrolysis of arachidonic acid containing phospholipid substrates releasing free arachidonic acid and lysophospholipids and giving rise to the generation of diverse lipid mediators involved in inflammatory conditions. Thus, the development of potent and selective GIVA cPLA2 inhibitors is of great importance. We have developed a novel class of such inhibitors based on the 2-oxoester functionality. This functionality in combination with a long aliphatic chain or a chain carrying an appropriate aromatic system, such as the biphenyl system, and a free carboxyl group leads to highly potent and selective GIVA cPLA2 inhibitors (X I(50) values 0.00007–0.00008) and docking studies aid in understanding this selectivity. A methyl 2-oxoester, with a short chain carrying a naphthalene ring, was found to preferentially inhibit the other major intracellular PLA2, the calcium-independent PLA2. In RAW264.7 macrophages, treatment with the most potent 2-oxoester GIVA cPLA2 inhibitor resulted in over 50% decrease in KLA-elicited prostaglandin D2 production. The novel, highly potent and selective GIVA cPLA2 inhibitors provide excellent tools for the study of the role of the enzyme and could contribute to the development of novel therapeutic agents for the treatment of inflammatory diseases.Maroula G. KokotouGerasimia GaliatsatouVictoria MagriotiGiorgos KoutoulogenisEfrosini BarbayianniDimitris LimniosVarnavas D. MouchlisBanita SatpathyAaron NavratilEdward A. DennisGeorge KokotosNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-16 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Maroula G. Kokotou Gerasimia Galiatsatou Victoria Magrioti Giorgos Koutoulogenis Efrosini Barbayianni Dimitris Limnios Varnavas D. Mouchlis Banita Satpathy Aaron Navratil Edward A. Dennis George Kokotos 2-Oxoesters: A Novel Class of Potent and Selective Inhibitors of Cytosolic Group IVA Phospholipase A2
description	Abstract Cytosolic phospholipase A2 (GIVA cPLA2) is the only PLA2 that exhibits a marked preference for hydrolysis of arachidonic acid containing phospholipid substrates releasing free arachidonic acid and lysophospholipids and giving rise to the generation of diverse lipid mediators involved in inflammatory conditions. Thus, the development of potent and selective GIVA cPLA2 inhibitors is of great importance. We have developed a novel class of such inhibitors based on the 2-oxoester functionality. This functionality in combination with a long aliphatic chain or a chain carrying an appropriate aromatic system, such as the biphenyl system, and a free carboxyl group leads to highly potent and selective GIVA cPLA2 inhibitors (X I(50) values 0.00007–0.00008) and docking studies aid in understanding this selectivity. A methyl 2-oxoester, with a short chain carrying a naphthalene ring, was found to preferentially inhibit the other major intracellular PLA2, the calcium-independent PLA2. In RAW264.7 macrophages, treatment with the most potent 2-oxoester GIVA cPLA2 inhibitor resulted in over 50% decrease in KLA-elicited prostaglandin D2 production. The novel, highly potent and selective GIVA cPLA2 inhibitors provide excellent tools for the study of the role of the enzyme and could contribute to the development of novel therapeutic agents for the treatment of inflammatory diseases.
format	article
author	Maroula G. Kokotou Gerasimia Galiatsatou Victoria Magrioti Giorgos Koutoulogenis Efrosini Barbayianni Dimitris Limnios Varnavas D. Mouchlis Banita Satpathy Aaron Navratil Edward A. Dennis George Kokotos
author_facet	Maroula G. Kokotou Gerasimia Galiatsatou Victoria Magrioti Giorgos Koutoulogenis Efrosini Barbayianni Dimitris Limnios Varnavas D. Mouchlis Banita Satpathy Aaron Navratil Edward A. Dennis George Kokotos
author_sort	Maroula G. Kokotou
title	2-Oxoesters: A Novel Class of Potent and Selective Inhibitors of Cytosolic Group IVA Phospholipase A2
title_short	2-Oxoesters: A Novel Class of Potent and Selective Inhibitors of Cytosolic Group IVA Phospholipase A2
title_full	2-Oxoesters: A Novel Class of Potent and Selective Inhibitors of Cytosolic Group IVA Phospholipase A2
title_fullStr	2-Oxoesters: A Novel Class of Potent and Selective Inhibitors of Cytosolic Group IVA Phospholipase A2
title_full_unstemmed	2-Oxoesters: A Novel Class of Potent and Selective Inhibitors of Cytosolic Group IVA Phospholipase A2
title_sort	2-oxoesters: a novel class of potent and selective inhibitors of cytosolic group iva phospholipase a2
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/0316803c50ec492b8ba589202502cf1b
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2-Oxoesters: A Novel Class of Potent and Selective Inhibitors of Cytosolic Group IVA Phospholipase A2

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