Novel benzoxanthene lignans that favorably modulate lipid mediator biosynthesis: A promising pharmacological strategy for anti-inflammatory therapy

摘要

Lipid mediators (LM) encompass pro-inflammatory prostaglandins (PG) and leukotrienes (LT) but also specialized pro-resolving mediators (SPM) which display pivotal bioactivities in health and disease. Pharmacological intervention with inflammatory disorders such as osteoarthritis and rheumatoid arthritis commonly employs anti-inflammatory drugs that can suppress PG and LT formation, which however, possess limited effectiveness and side effects. Here, we report on the discovery and characterization of the two novel benzoxanthene lignans 1 and 2 that modulate select LM biosynthetic enzymes enabling the switch from pro-inflammatory LT to SPM biosynthesis as potential pharmacological strategy to intervene with inflammation. In cell-free assays, compound 1 and 2 inhibit microsomal prostaglandin E-2 synthase-1 and leukotriene C-4 synthase (IC50 similar to 0.6-3.4 mu M) and potently interfere with 5-lipoxygenase (5-LOX), the key enzyme in LT biosynthesis (IC50 = 0.04 and 0.09 mu M). In human neutrophils, monocytes and M1 and M2 macrophages, compound 1 and 2 efficiently suppress LT biosynthesis (IC50 < 1 mu M), accompanied by elevation of 15-LOX-derived LM including SPM. In zymosan-induced murine peritonitis, compound 1 and 2 ameliorated self-limited inflammation along with suppression of early LT formation and elevation of subsequent SPM biosynthesis in vivo. Together, these novel benzoxanthene lignans promote the LM class switch from pro-inflammatory towards pro-resolving LM to terminate inflammation, suggesting their suitability as novel leads for pharmacotherapy of arthritis and related inflammatory disorders.