Τίτλος:
Evaluation of Dual 5-Lipoxygenase/Microsomal Prostaglandin E2 Synthase-1 Inhibitory Effect of Natural and Synthetic Acronychia-Type Isoprenylated Acetophenones
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. © 2017 The American Chemical Society and American Society of Pharmacognosy.
Συγγραφείς:
Svouraki, A.
Garscha, U.
Kouloura, E.
Pace, S.
Pergola, C.
Krauth, V.
Rossi, A.
Sautebin, L.
Halabalaki, M.
Werz, O.
Gaboriaud-Kolar, N.
Skaltsounis, A.-L.
Περιοδικό:
Tropical Journal of Natural Product Research
Εκδότης:
American Chemical Society
Λέξεις-κλειδιά:
3 [3 tert butylthio 1 (4 chlorobenzyl) 5 isopropyl 2 indolyl] 2,2 dimethylpropionic acid; acetophenone derivative; arachidonate 5 lipoxygenase activating protein inhibitor; indometacin; isomerase inhibitor; natural product; zileuton; acetophenone derivative; antiinflammatory agent; arachidonate 5 lipoxygenase; hydroxyurea; isomerase; lipoxygenase inhibitor; prostaglandin E synthase; zileuton, animal experiment; animal model; antiinflammatory activity; controlled study; drug potency; drug screening; drug synthesis; experimental model; human; human cell; in vitro study; male; mouse; nonhuman; Review; structure activity relation; analogs and derivatives; animal; antagonists and inhibitors; chemical structure; chemistry; disease model; drug effects; IC50; isolation and purification; metabolism; prenylation; Rutaceae, Acetophenones; Animals; Anti-Inflammatory Agents; Arachidonate 5-Lipoxygenase; Disease Models, Animal; Humans; Hydroxyurea; Inhibitory Concentration 50; Intramolecular Oxidoreductases; Lipoxygenase Inhibitors; Mice; Molecular Structure; Prenylation; Prostaglandin-E Synthases; Rutaceae; Structure-Activity Relationship
DOI:
10.1021/acs.jnatprod.6b01008
