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

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-LXA 4 -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.

Formylpeptide receptor 2: Nomenclature, structure, signalling and translational perspectives: IUPHAR review 35

“…This has created debate around the ability of endogenous ligands (e.g. LXA 4 ) to generate FPR2 signalling (de Gaetano et al, 2019, 2021; Merlin et al, 2022). It is possible there is a disconnect between heterologous‐ versus endogenous‐expressed FPR2 or allosteric modes of receptor interaction (Ge, Liao, et al, 2020), that once fully explored in light of publication of FPR2 structure (Chen et al, 2020; Zhuang et al, 2020), may provide an explanation for these apparent discrepancies.…”

Synthesis and Biological Evaluation of Bicyclo[1.1.1]pentane-Containing Aromatic Lipoxin A4 Analogues

“…The synthesis of boronic ester 10 was recently reported by us for the synthesis of our quinoxaline LXA 4 analogues. 10 The modular nature of our retrosynthetic strategy means that the same coupling partner can easily be used in a number of different Suzuki reactions to produce a wide array of different heteroaromatic LXA 4 mimetics, including the target BCP-containing analogues. With boronic ester 10 in hand, we turned our attention to the synthesis of the BCP-containing lower chain unit 9 ( Scheme 2 ).…”

“…These have included pyridine, oxazole, imidazole ( 3 ), and quinoxaline ( 4 ) analogues that have shown favorable anti-inflammatory properties comparable or superior to those of native LXA 4 (Figure ). − As part of our ongoing structure–activity relationship (SAR) studies, we sought to explore the effect of incorporating a bicyclo[1.1.1]­pentane (BCP) moiety into the lower C-16–C-20 alkyl chain of our (hetero)­aromatic LXA 4 mimetics. In recent years, there has been significant interest in BCPs as sp 3 -rich surrogates within potentially bioactive molecules for para -substituted arenes as well as for tert -butyl groups and alkynes. − We wanted to determine whether a BCP ring could also serve as a more rigid and metabolically resistant bioisostere for alkyl chains in fatty acid-derived molecules.…”

Asymmetric Synthesis of Benzothiophene-Containing Lipoxin A4 Analogues with Lower-Chain Modifications

“…These have included a benzo-LXA4 analogue as well as various pyridine, oxazole, imidazole and quinoxaline analogues (2-5, Figure 1). [8][9][10][11] We have also investigated the synthesis of aromatic LXA4 analogues with novel modifications to the lower alkyl chain of the molecule.…”

“…These have included a benzo-LXA 4 analogue as well as various pyridine, oxazole, imidazole, and quinoxaline analogues 2-5 (Figure 1). [8][9][10][11] We have also investigated the synthesis of aromatic LXA 4 analogues with novel modifications to the lower alkyl chain of the molecule. 12 Many of these analogues have been shown to possess significantly enhanced anti-inflammatory properties relative to native LXA 4 .…”