Synthesis and pharmacological evaluation of a selected library of new potential anti-inflammatory agents bearing the gamma-hydroxybutenolide scaffold: a new class of inhibitors of prostanoid production through the selective modulation of microsomal prostaglandin E synthase-1 expression.
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.
Guerrero
Maria D
MD
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Salerno, Via Ponte Don Melillo, 84084 Fisciano (SA), Italy.
Aquino
Maurizio
M
Bruno
Ines
I
Terencio
María C
MC
Paya
Miguel
M
Riccio
Raffaele
R
Gomez-Paloma
Luigi
L
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D020650:Combinatorial Chemistry Techniques; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D015232:Dinoprostone / Q000096:biosynthesis; D005260:Female; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors*; D051379:Mice; D008861:Microsomes / Q000201:enzymology*; D016328:NF-kappa B / Q000378:metabolism; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D054467:Phospholipases A2; D011448:Prostaglandin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000071876:Prostaglandin-E Synthases; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C520645:4-benzo(b)thiophen-2-yl-3-bromo-5-hydroxy-5H-furan-2-one; D000894:Anti-Inflammatory Agents, Non-Steroidal; D005663:Furans; D016328:NF-kappa B; D011448:Prostaglandin Antagonists; D013876:Thiophenes; D051546:Cyclooxygenase 2; D010741:Phospholipases A; D054467:Phospholipases A2; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone; D015107:4-Butyrolactone