Asymmetric Synthesis and Biological Evaluation of 1,3‐ and 1,4‐Disubstituted Isoquinoline‐Containing Lipoxin A4 Analogues

(1R)- and (1S)-Epimers of novel isoquinoline-derived SPMs were prepared, with a Pd-catalyzed Heck reaction and a Ru(II)-catalyzed asymmetric transfer hydrogenation as the key synthetic steps. Biological assessment demonstrated that several analogues significantly attenuate lipopolysaccharide-induced NF-κB activation and downstream pro-inflammatory cytokine secretion, including IL-6, IL-1β, and TNF.

Abstract

The resolution of inflammation is increasingly recognized as an active, highly regulated process essential for restoring tissue homeostasis following immune activation. Lipoxin-A₄ (LXA₄), an endogenous specialized pro-resolving mediator (SPM), plays a central role in this process through activation of the ALX/FPR2 receptor. However, its clinical application is limited by rapid metabolic degradation and poor in vivo stability. In this study, we report the design, asymmetric synthesis, and biological evaluation of novel 1,3- and 1,4-disubstituted isoquinoline-based analogues of LXA₄ (Isoq-sLXms), designed to enhance metabolic stability. The synthetic route employed a palladium-catalyzed Heck cross-coupling and Ru(II)-catalyzed asymmetric transfer hydrogenation, affording diastereomerically pure compounds. Biological assessment in THP-1 LUCIA monocytes demonstrated that several analogues, particularly (1R)-8, significantly attenuate lipopolysaccharide (LPS)-induced NF-κB activation and downstream pro-inflammatory cytokine secretion, including IL-6, IL-1β, and TNF. Functional assays using ALX/FPR2-transfected HEK-293 cells revealed that (1R)-8 acts as a partial agonist, supporting its role in engaging pro-resolving signaling mechanisms. Safety profiling confirmed low cytotoxicity across physiologically relevant concentrations. These findings demonstrate that isoquinoline-based LXA₄ mimetics retain and enhance key pro-resolving bioactivities while offering improved stability and receptor selectivity. (1R)-8 emerges as a promising lead compound for the development of resolution-directed therapeutics in the context of chronic inflammation.

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