Details

Autor(en) / Beteiligte

• De Simone, Rosa
• Andrés, Rosa M
• Aquino, Maurizio
• Bruno, Ines
• Guerrero, María D
• Terencio, María C
• Paya, Miguel
• Riccio, Raffaele

Titel

Toward the Discovery of New Agents Able to Inhibit the Expression of Microsomal Prostaglandin E Synthase-1 Enzyme as Promising Tools in Drug Development

Ist Teil von

• Chemical biology & drug design, 2010-07, Vol.76 (1), p.17-24

Ort / Verlag

Oxford, UK: Oxford, UK : Blackwell Publishing Ltd

Erscheinungsjahr

2010

Link zum Volltext

Quelle

Wiley Online Library Journals Frontfile Complete

Beschreibungen/Notizen

• In our recent studies, we focused our attention on the synthesis of several γ-hydroxybutenolides designed on the basis of petrosaspongiolide M 1 (PM) structure that has been recognized to potently inhibit the inflammatory process through the selective PLA₂ 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 PLA₂ 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 γ-hydroxybutenolide 2, which so far represents the only product, together with resveratrol, able to reduce PGE₂ 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 γ-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 PGE₂ production on mouse macrophage cell line RAW264.7 through the selective modulation of mPGES-1 enzyme expression.