title: Evaluation of Dual 5-Lipoxygenase/Microsomal Prostaglandin E2 Synthase-1 Inhibitory Effect of Natural and Synthetic Acronychia-Type Isoprenylated Acetophenones.
abstract: Among the pathways responsible for the development of inflammatory responses, the cyclooxygenase and lipoxygenase pathways are among the most important ones. Two key enzymes, namely, 5-LO and mPGES-1, are involved in the biosynthesis of leukotrienes and prostaglandins, respectively, which are considered attractive therapeutic targets, so their dual inhibition might be an effective strategy to control inflammatory deregulation. Several natural products have been identified as 5-LO inhibitors, with some also being dual 5-LO/mPGES-1 inhibitors. Here, some prenylated acetophenone dimers from Acronychia pedunculata have been identified for their dual inhibitory potency toward 5-LO and mPGES-1. To gain insight into the SAR of this family of natural products, the synthesis and biological evaluation of analogues are presented. The results show the ability of the natural and synthetic molecules to potently inhibit 5-LO and mPEGS-1 in vitro. The potency of the most active compound (10) has been evaluated in vivo in an acute inflammatory mouse model and displayed potent anti-inflammatory activity comparable in potency to the drug zileuton used as a positive control.
authors.affiliation: Department of Pharmacognosy and Natural Products Chemistry, School of Pharmacy, University of Athens, Panepistimiopolis Zografou , GR-15771, Athens, Greece.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Svouraki
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University , 07743 Jena, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Garscha
authors.affiliation: Department of Pharmacognosy and Natural Products Chemistry, School of Pharmacy, University of Athens, Panepistimiopolis Zografou , GR-15771, Athens, Greece.
authors.forename: Eirini
authors.initials: E
authors.lastname: Kouloura
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University , 07743 Jena, Germany.
authors.forename: Simona
authors.initials: S
authors.lastname: Pace
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University , 07743 Jena, Germany.
authors.forename: Carlo
authors.initials: C
authors.lastname: Pergola
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University , 07743 Jena, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Krauth
authors.affiliation: Department of Pharmacy, University of Naples Federico II , Naples, Italy.
authors.forename: Antonietta
authors.initials: A
authors.lastname: Rossi
authors.affiliation: Department of Pharmacy, University of Naples Federico II , Naples, Italy.
authors.forename: Lidia
authors.initials: L
authors.lastname: Sautebin
authors.affiliation: Department of Pharmacognosy and Natural Products Chemistry, School of Pharmacy, University of Athens, Panepistimiopolis Zografou , GR-15771, Athens, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Halabalaki
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University , 07743 Jena, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
authors.affiliation: Department of Pharmacognosy and Natural Products Chemistry, School of Pharmacy, University of Athens, Panepistimiopolis Zografou , GR-15771, Athens, Greece.
authors.forename: Nicolas
authors.identifier: 0000-0001-9307-1921
authors.initials: N
authors.lastname: Gaboriaud-Kolar
authors.affiliation: Department of Pharmacognosy and Natural Products Chemistry, School of Pharmacy, University of Athens, Panepistimiopolis Zografou , GR-15771, Athens, Greece.
authors.forename: Alexios-Leandros
authors.initials: AL
authors.lastname: Skaltsounis
mesh_terms: D000098:Acetophenones / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001094:Arachidonate 5-Lipoxygenase / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D054876:Prenylation; D000071876:Prostaglandin-E Synthases / Q000037:antagonists & inhibitors*; D027821:Rutaceae / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000098:Acetophenones; D000893:Anti-Inflammatory Agents; D016859:Lipoxygenase Inhibitors; D001094:Arachidonate 5-Lipoxygenase; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C063449:zileuton; D006918:Hydroxyurea