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

Authors :
Rao, Zhigang
Caprioglio, Diego
Gollowitzer, André
Kretzer, Christian
Imperio, Daniela
Collado, Juan A.
Waltl, Lorenz
Lackner, Sandra
Appendino, Giovanni
Muñoz, Eduardo
Temml, Veronika
Werz, Oliver
Minassi, Alberto
Koeberle, Andreas
Source :
Biochemical Pharmacology. Sep2022, Vol. 203, pN.PAG-N.PAG. 1p.
Publication Year :
2022

Abstract

[Display omitted] 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 E 2 synthase (mPGES)-1. These enzymes are critical for the production of pro-inflammatory leukotrienes and prostaglandin (PG)E 2 , 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 , IC 50 = 0.038 µM, 44.7-fold selectivity over mPGES-1) and mPGES-1 inhibitors (2f , IC 50 = 0.11 µM, 4.6-fold selectivity over 5-LOX). Molecular docking experiments suggest that the C 2-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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00062952
Volume :
203
Database :
Academic Search Index
Journal :
Biochemical Pharmacology
Publication Type :
Academic Journal
Accession number :
158607524
Full Text :
https://doi.org/10.1016/j.bcp.2022.115202