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

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 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 gamma-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,...