title: Toward the discovery of new agents able to inhibit the expression of microsomal prostaglandin E synthase-1 enzyme as promising tools in drug development.
abstract: In our recent studies, we focused our attention on the synthesis of several gamma-hydroxybutenolides designed on the basis of petrosaspongiolide M 1 (PM) structure that has been recognized to potently inhibit the inflammatory process through the selective PLA(2) enzyme inhibition. By means of a combination of computational methods and efficient synthetic strategies, we generated small collections of PM modified analogs to identify new potent PLA(2) inhibitors, suitable for clinical development. In the course of the biological screening of our compounds, we discovered a potent and selective inhibitor of mPGES-1 expression, the benzothiophene gamma-hydroxybutenolide 2, which so far represents the only product, together with resveratrol, able to reduce PGE(2) production through the selective downregulation of mPGES-1 enzyme. In consideration that microsomal prostaglandin E synthase 1 (mPGES-1) is one of the most strategic target involved both in inflammation and in carcinogenesis processes, we decided to explore the biological effects of some structural changes of the gamma-hydroxybutenolide 2, hoping to improve its biological profile. This optimization process led to the identification of three strictly correlated compounds 14g, 16g, and 18 with higher inhibitory potency on PGE(2) production on mouse macrophage cell line RAW264.7 through the selective modulation of mPGES-1 enzyme expression.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Salerno, 84084 Fisciano (SA), Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: De Simone
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Andrés
authors.forename: Maurizio
authors.initials: M
authors.lastname: Aquino
authors.forename: Ines
authors.initials: I
authors.lastname: Bruno
authors.forename: María D
authors.initials: MD
authors.lastname: Guerrero
authors.forename: María C
authors.initials: MC
authors.lastname: Terencio
authors.forename: Miguel
authors.initials: M
authors.lastname: Paya
authors.forename: Raffaele
authors.initials: R
authors.lastname: Riccio
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics; D015232:Dinoprostone / Q000378:metabolism; D055808:Drug Discovery; D015870:Gene Expression / Q000187:drug effects*; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008861:Microsomes / Q000187:drug effects* / Q000201:enzymology; D009828:Oleanolic Acid / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D000071876:Prostaglandin-E Synthases; D013876:Thiophenes / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C520645:4-benzo(b)thiophen-2-yl-3-bromo-5-hydroxy-5H-furan-2-one; D013876:Thiophenes; C118309:petrosaspongiolide m; C088015:benzothiophene; D009828:Oleanolic Acid; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone; D015107:4-Butyrolactone