Asymmetric synthesis and biological evaluation of imidazole- and oxazole-containing synthetic lipoxin A4 mimetics (sLXms).

Abstract

Lipoxins (LXs) are endogenously generated eicosanoids with potent bio-actions consistent with attenuation of inflammation. The costly synthesis and metabolic instability of LXs may limit their therapeutic potential. Here we report the synthesis and characterization of novel imidazole-/oxazole-containing synthetic-LX-mimetics (sLXms). The key steps of asymmetric synthesis of putative sLXms include a Suzuki reaction and an asymmetric ketone reduction. The effect of the novel compounds on inflammatory responses was assessed using a human monocyte cell line stably expressing a Nuclear Factor Kappa B (NFkB) reporter gene, by investigating downstream cytokine secretion. The potential interaction of the imidazoles/oxazoles with the molecular target of LXs, i.e. G-protein coupled receptor (GPCR) Formyl Peptide Receptor 2 (ALX/FPR2) was investigated using a cell system where ALX/FPR2 is coupled to the Gαq subunit and receptor interaction determined by mobilisation of intracellular calcium. In vivo anti-inflammatory effects were assessed using a murine zymosan-induced peritonitis model. Overall, structure-activity relationship (SAR) studies demonstrated that the (R)-epimer of 6C-dimethyl-imidazole (1R)-11 was the most potent and efficient anti-inflammatory agent, among the ten compounds tested. This molecule significantly attenuated LPS-induced NFkB activity, reduced the release of several pro-inflammatory cytokines and inhibited peritonitis-associated neutrophil infiltration in vivo. The underlying mechanism for those actions appeared to be through FPR2 activation. These data support the therapeutic potential of imidazole-containing sLXms in the context of novel inflammatory regulators.

• Authors: Monica de Gaetano, Eibhlín Butler, Kevin Gahan, Andrea Zanetti, Mariam Marai, Jianmin Chen, Antonino Cacace, Emily Hams, Catherine Maingot, Alisha McLoughlin, Eoin Brennan, Xavier Leroy, Christine E Loscher, Padraic Fallon, Mauro Perretti, Catherine Godson, Patrick J Guiry
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 162 Pg. 80-108 (Jan 15 2019) ISSN: 1768-3254 [Electronic] France
• PMID: 30419493 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Chemical References

• Imidazoles
• Lipoxins
• NF-kappa B
• Oxazoles
• Receptors, Formyl Peptide
• formyl peptide receptor 2, mouse
• lipoxin A4
• imidazole

Topics

• Animals
• Cell Line
• Humans
• Imidazoles (chemistry)
• Inflammation (drug therapy)
• Lipoxins (chemical synthesis, pharmacology)
• Mice
• Molecular Mimicry
• Monocytes (drug effects, metabolism)
• NF-kappa B (metabolism)
• Oxazoles (chemistry)
• Peritonitis (drug therapy)
• Receptors, Formyl Peptide (metabolism)