Abstract
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 gamma-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 gamma-hydroxybutenolide scaffold. The synthesized products were tested for their ability to inhibit PLA2 enzymes 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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4-Butyrolactone / analogs & derivatives*
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4-Butyrolactone / chemical synthesis
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4-Butyrolactone / chemistry
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4-Butyrolactone / pharmacology
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Cell Line
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Combinatorial Chemistry Techniques
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Cyclooxygenase 2 / biosynthesis
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Dinoprostone / biosynthesis
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Female
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Furans / chemical synthesis*
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Furans / chemistry
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Furans / pharmacology
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Humans
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Intramolecular Oxidoreductases / antagonists & inhibitors*
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Mice
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Microsomes / enzymology*
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NF-kappa B / metabolism
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Phospholipases A / antagonists & inhibitors
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Phospholipases A2
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Prostaglandin Antagonists / chemical synthesis*
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Prostaglandin Antagonists / chemistry
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Prostaglandin Antagonists / pharmacology
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Prostaglandin-E Synthases
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Structure-Activity Relationship
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Thiophenes / chemical synthesis*
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Thiophenes / chemistry
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Thiophenes / pharmacology
Substances
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4-benzo(b)thiophen-2-yl-3-bromo-5-hydroxy-5H-furan-2-one
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Anti-Inflammatory Agents, Non-Steroidal
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Furans
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NF-kappa B
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Prostaglandin Antagonists
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Thiophenes
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Cyclooxygenase 2
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Phospholipases A
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Phospholipases A2
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Intramolecular Oxidoreductases
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PTGES protein, human
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Prostaglandin-E Synthases
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Ptges protein, mouse
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Dinoprostone
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4-Butyrolactone