title: SAR studies on curcumin's pro-inflammatory targets: discovery of prenylated pyrazolocurcuminoids as potent and selective novel inhibitors of 5-lipoxygenase.
abstract: The anticarcinogenic and anti-inflammatory properties of curcumin have been extensively investigated, identifying prostaglandin E2 synthase (mPGES)-1 and 5-lipoxygenase (5-LO), key enzymes linking inflammation with cancer, as high affinity targets. A comparative structure-activity study revealed three modifications dissecting mPGES-1/5-LO inhibition, namely (i) truncation of the acidic, enolized dicarbonyl moiety and/or replacement by pyrazole, (ii) hydrogenation of the interaryl linker, and (iii) (dihydro)prenylation. The prenylated pyrazole analogue 11 selectively inhibited 5-LO, outperforming curcumin by a factor of up to 50, and impaired zymosan-induced mouse peritonitis along with reduced 5-LO product levels. Other pro-inflammatory targets of curcumin (i.e., mPGES-1, cyclooxygenases, 12/15-LOs, nuclear factor-κB, nuclear factor-erythroid 2-related factor-2, and signal transducer and activator of transcription 3) were hardly affected by 11. The strict structural requirements for mPGES-1 and 5-LO inhibition strongly suggest that specific interactions rather than redox or membrane effects underlie the inhibition of mPGES-1 and 5-LO by curcumin.
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University Jena , Philosophenweg 14, 07743 Jena, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Koeberle
authors.forename: Eduardo
authors.initials: E
authors.lastname: Muñoz
authors.forename: Giovanni B
authors.initials: GB
authors.lastname: Appendino
authors.forename: Alberto
authors.initials: A
authors.lastname: Minassi
authors.forename: Simona
authors.initials: S
authors.lastname: Pace
authors.forename: Antonietta
authors.initials: A
authors.lastname: Rossi
authors.forename: Christina
authors.initials: C
authors.lastname: Weinigel
authors.forename: Dagmar
authors.initials: D
authors.lastname: Barz
authors.forename: Lidia
authors.initials: L
authors.lastname: Sautebin
authors.forename: Diego
authors.initials: D
authors.lastname: Caprioglio
authors.forename: Juan A
authors.initials: JA
authors.lastname: Collado
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D003474:Curcumin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D010538:Peritonitis / Q000188:drug therapy; D013329:Structure-Activity Relationship
chemical_list: D000893:Anti-Inflammatory Agents; D016859:Lipoxygenase Inhibitors; D001094:Arachidonate 5-Lipoxygenase; D003474:Curcumin