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Asymmetric Synthesis and Biological Screening of Quinoxaline-Containing Synthetic Lipoxin A₄ Mimetics (QNX-sLXms)

De Gaetano, M; Tighe, C; Gahan, K; Zanetti, A; Chen, J; Newson, J; Cacace, A; ... Guiry, PJ; + view all (2021) Asymmetric Synthesis and Biological Screening of Quinoxaline-Containing Synthetic Lipoxin A₄ Mimetics (QNX-sLXms). Journal of Medicinal Chemistry 10.1021/acs.jmedchem.1c00403. (In press). Green open access

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Abstract

Failure to resolve inflammation underlies many prevalent pathologies. Recent insights have identified lipid mediators, typified by lipoxins (LXs), as drivers of inflammation resolution, suggesting potential therapeutic benefit. We report the asymmetric preparation of novel quinoxaline-containing synthetic-LXA4-mimetics (QNX-sLXms). Eight novel compounds were screened for their impact on inflammatory responses. Structure–activity relationship (SAR) studies showed that (R)-6 (also referred to as AT-02-CT) was the most efficacious and potent anti-inflammatory compound of those tested. (R)-6 significantly attenuated lipopolysaccharide (LPS)- and tumor-necrosis-factor-α (TNF-α)-induced NF-κB activity in monocytes and vascular smooth muscle cells. The molecular target of (R)-6 was investigated. (R)-6 activated the endogenous LX receptor formyl peptide receptor 2 (ALX/FPR2). The anti-inflammatory properties of (R)-6 were further investigated in vivo in murine models of acute inflammation. Consistent with in vitro observations, (R)-6 attenuated inflammatory responses. These results support the therapeutic potential of the lead QNX-sLXm (R)-6 in the context of novel inflammatory regulators.

Type: Article
Title: Asymmetric Synthesis and Biological Screening of Quinoxaline-Containing Synthetic Lipoxin A₄ Mimetics (QNX-sLXms)
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1021/acs.jmedchem.1c00403
Publisher version: https://doi.org/10.1021/acs.jmedchem.1c00403
Language: English
Additional information: This is an Open Access article published under a Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/).
Keywords: Peptides and proteins, Inorganic compounds, Antiinflammatories, Particulate matter, Inflammation
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Experimental and Translational Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/10130437
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