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Rotational constriction of curcuminoids impacts 5-lipoxygenase and mPGES-1 inhibition and evokes a lipid mediator class switch in macrophages.

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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

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Elsevier
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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.

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MeSH Terms

Arachidonate 5-lipoxygenase
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

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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