摘要：

As a part of our drug discovery effort, recently we clarified the molecular basis of phospholipase A2(PLA2) inactivation by petrosaspongiolide M (PM), an interesting metabolite belonging to a marine sesterterpene family, containing in its structural architecture a -hydroxybutenolide moiety and showing potent anti-inflammatory activity. In the attempt to expand structural diversity as well as to simplify crucial synthetic features of the parent compound, we decided to develop a selected library based on the densely functionalized -hydroxybutenolide scaffold. The synthesized products were tested for their ability to inhibit PLA2enzymes as well as to modulate the expression of inducible cyclooxygenase 2 (COX-2) and microsomal prostaglandin E synthase 1 (mPGES-1), two key enzymes highly involved in the inflammatory event, in order to discover new promising anti-inflammatory agents with better pharmacological profiles. This led us to the discovery of a promising inhibitor (4e) of prostanoid production acting by in vitro and in vivo selective modulation of microsomal prostaglandin E synthase 1 expression.

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