Publication: Rotational constriction of curcuminoids impacts 5-lipoxygenase and mPGES-1 inhibition and evokes a lipid mediator class switch in macrophages.
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Identifiers
Date
2022-07-29
Authors
Rao, Zhigang
Caprioglio, Diego
Gollowitzer, Andre
Kretzer, Christian
Imperio, Daniela
Collado, Juan A
Waltl, Lorenz
Lackner, Sandra
Appendino, Giovanni
Muñoz, Eduardo
Advisors
Journal Title
Journal ISSN
Volume Title
Publisher
Elsevier
Abstract
Polypharmacological targeting of lipid mediator networks offers potential for efficient and safe anti-inflammatory therapy. Because of the diversity of its biological targets, curcumin (1a) has been viewed as a privileged structure for bioactivity or, alternatively, as a pan-assay interference (PAIN) compound. Curcumin has actually few high-affinity targets, the most remarkable ones being 5-lipoxygenase (5-LOX) and microsomal prostaglandin E2 synthase (mPGES)-1. These enzymes are critical for the production of pro-inflammatory leukotrienes and prostaglandin (PG)E2, and previous structure-activity-relationship studies in this area have focused on the enolized 1,3-diketone motif, the alkyl-linker and the aryl-moieties, neglecting the rotational state of curcumin, which can adopt twisted conformations in solution and at target sites. To explore how the conformation of curcuminoids impacts 5-LOX and mPGES-1 inhibition, we have synthesized rotationally constrained analogues of the natural product and its pyrazole analogue by alkylation of the linker and/or of the ortho aromatic position(s). These modifications strongly impacted 5-LOX and mPGES-1 inhibition and their systematic analysis led to the identification of potent and selective 5-LOX (3b, IC50 = 0.038 µM, 44.7-fold selectivity over mPGES-1) and mPGES-1 inhibitors (2f, IC50 = 0.11 µM, 4.6-fold selectivity over 5-LOX). Molecular docking experiments suggest that the C2-methylated pyrazolocurcuminoid 3b targets an allosteric binding site at the interface between catalytic and regulatory 5-LOX domain, while the o, o'-dimethylated desmethoxycurcumin 2f likely binds between two monomers of the trimeric mPGES-1 structure. Both compounds trigger a lipid mediator class switch from pro-inflammatory leukotrienes to PG and specialized pro-resolving lipid mediators in activated human macrophages.
Description
MeSH Terms
Arachidonate 5-lipoxygenase
Constriction
Curcumin
Diarylheptanoids
Eicosanoids
Humans
Leukotrienes
Lipoxygenase inhibitors
Macrophages
Molecular docking simulation
Prostaglandin-E synthases
Prostaglandins
Constriction
Curcumin
Diarylheptanoids
Eicosanoids
Humans
Leukotrienes
Lipoxygenase inhibitors
Macrophages
Molecular docking simulation
Prostaglandin-E synthases
Prostaglandins
DeCS Terms
Araquidonato 5-lipooxigenasa
Constricción
Curcumina
Diarilheptanoides
Inhibidores de la lipooxigenasa
Leucotrienos
Macrófagos
Constricción
Curcumina
Diarilheptanoides
Inhibidores de la lipooxigenasa
Leucotrienos
Macrófagos
CIE Terms
Keywords
Curcumin, Inflammation, Leukotriene, Lipid mediators, Natural product, Structure–activity relationship
Citation
Rao Z, Caprioglio D, Gollowitzer A, Kretzer C, Imperio D, Collado JA, et al. Rotational constriction of curcuminoids impacts 5-lipoxygenase and mPGES-1 inhibition and evokes a lipid mediator class switch in macrophages. Biochem Pharmacol. 2022 Sep;203:115202