Development of a second generation of inhibitors of microsomal prostaglandin E synthase 1 expression bearing the gamma-hydroxybutenolide scaffold.
Petrosaspongiolide M (PM), a marine sesterterpene metabolite bearing the gamma-hydroxybutenolide scaffold and displaying a potent inhibitory activity toward PLA(2) enzyme, was selected by us as an attractive target in order to explore its mechanism of action at molecular level. In the course of our investigations we decided to synthetically modify the parent compound to clarify the structural determinants responsible for the activity; in fact, very recently, our research group reported the synthesis and the pharmacological properties of a first collection of PM analogues generated by Ludi approach. The synthesized compounds showed a poor or moderate activity toward PLA(2) enzymes, nevertheless we discovered a potent and selective modulator of the expression of microsomal prostaglandin E synthase 1 (mPGES-1), an enzyme highly involved in the inflammatory response, which represents an interesting target for the development of a new class of anti-inflammatory agents. In this paper we report the synthesis of a further collection of nine analogues, having the same scaffold of PM, the gamma-hydroxybutenolide, and bearing, as side chain, more complex aromatic portions, in substitution of the sesterterpene moiety. Their pharmacological behavior against PLA(2) enzymes as well as to modulate the expression of inducible cyclooxygenase 2 (COX-2) and mPGES-1 enzymes is also described.
Aquino
Maurizio
M
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Salerno, Via Ponte Don Melillo, 84084 Fisciano, SA, Italy.
Guerrero
Maria D
MD
Bruno
Ines
I
Terencio
María C
MC
Paya
Miguel
M
Riccio
Raffaele
R
D015107:4-Butyrolactone / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D005786:Gene Expression Regulation; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008861:Microsomes / Q000187:drug effects* / Q000201:enzymology; D054467:Phospholipases A2 / Q000737:chemistry / Q000378:metabolism; D011448:Prostaglandin Antagonists / Q000138:chemical synthesis / Q000494:pharmacology*; D000071876:Prostaglandin-E Synthases; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D011448:Prostaglandin Antagonists; D051546:Cyclooxygenase 2; D054467:Phospholipases A2; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015107:4-Butyrolactone