RT Journal Article
T1 Rotational constriction of curcuminoids impacts 5-lipoxygenase and mPGES-1 inhibition and evokes a lipid mediator class switch in macrophages.
A1 Rao, Zhigang
A1 Caprioglio, Diego
A1 Gollowitzer, Andre
A1 Kretzer, Christian
A1 Imperio, Daniela
A1 Collado, Juan A
A1 Waltl, Lorenz
A1 Lackner, Sandra
A1 Appendino, Giovanni
A1 Muñoz, Eduardo
A1 Temml, Veronika
A1 Werz, Oliver
A1 Minassi, Alberto
A1 Koeberle, Andreas
K1 Curcumin
K1 Inflammation
K1 Leukotriene
K1 Lipid mediators
K1 Natural product
K1 Structure–activity relationship
AB 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.
PB Elsevier
YR 2022
FD 2022-07-29
LK http://hdl.handle.net/10668/22029
UL http://hdl.handle.net/10668/22029
LA en
NO 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
NO The authors thank Katrin Fischer, Monika Listing, Barbel ¨ Schmalwasser and Saskia Schmidt for technical assistance in performing experiments.This research was funded in part by the Austrian Science Fund (FWF)(I4968-B), the Tyrolean Science Fund (TWF) (F.33467/7-2021), Bionorica Research GmbH (project number 320092), Deutsche  orschungsgemeinschaft (DFG) and Collaborative Research Center SFB 1278 “PolyTarget” (project number 316213987, project A04). V.T. was funded by the Austrian Science Fund (FWF) project T942. For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.
DS RISalud
RD Apr 18, 2025