Novel benzoxanthene lignans that favorably modulate lipid mediator biosynthesis: A promising pharmacological strategy for anti-inflammatory therapy
Novel benzoxanthene lignans that favorably modulate lipid mediator biosynthesis: A promising pharmacological strategy for anti-inflammatory therapy
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DOI：
10.1016/j.bcp.2019.03.003
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发表时间：
2019-07-01
影响因子：
5.8
通讯作者：
Pace, Simona
中科院分区：
文献类型：
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作者：
Gerstmeier, Jana;Kretzer, Christian;Pace, Simona
脂质介质（LM）包括促炎性的白藜芦醇（PG）和白三烯（LT），但也包括在健康和疾病中显示关键生物活性的专门的促消退介质（SPM）。对炎性疾病如骨关节炎和类风湿性关节炎的药理学干预通常采用可以抑制PG和LT形成的抗炎药物，然而，其具有有限的有效性和副作用。在这里，我们报告的发现和表征的两种新的苯并咕吨木脂素1和2，调节选择LM生物合成酶，使开关从促炎LT SPM生物合成作为潜在的药理学策略，干预炎症。在无细胞测定中，化合物1和2抑制微粒体前列腺素E-2合酶-1和白三烯C-4合酶（IC 50类似于0.6-3.4 μ M），并有效地干扰LT生物合成中的关键酶5-脂氧合酶（5-LOX）（IC 50 = 0.04和0.09 μ M）。在人嗜中性粒细胞、单核细胞和M1和M2巨噬细胞中，化合物1和2有效地抑制LT生物合成（IC 50 < 1 μ M），伴随着15-LOX衍生的LM（包括SPM）的升高。在酵母聚糖诱导的小鼠腹膜炎中，化合物1和2改善了自限性炎症沿着抑制早期LT形成和体内随后SPM生物合成的升高。总之，这些新的苯并咕吨木脂素促进LM类从促炎性向促消退LM转变以终止炎症，表明它们适合作为关节炎和相关炎性病症的药物治疗的新先导物。
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.