Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, China.
CAS Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, 510301, China.
Bioorg Chem. 2024 Apr;145:107209. doi: 10.1016/j.bioorg.2024.107209. Epub 2024 Feb 15.
Marine natural products continue to hold great promise as potential candidates for the discovery of anti-inflammatory drug. In our previous investigation, we successfully synthesized axinelline A, a naturally occurring cyclooxygenase-2 (COX-2) inhibitor, as a promising anti-inflammatory lead compound. This study was to discover novel COX inhibitors with balanced inhibition, aiming to mitigate the severe adverse effects through further structural modification of axinelline A. Of the synthetic derivatives, compound 5e showed highest COX-2 inhibitory activity and balanced COX inhibition (IC = 1.74 µM; selectivity ((IC (COX-1)/IC(COX-2) = 16.32). The in vitro anti-inflammatory results indicated that 5e effectively suppressed the expression of pro-inflammatory mediators via the NF-κB signaling pathway rather than the MAPK signaling pathway. The in vivo ulcerative colitis assay demonstrated 5e significantly ameliorated the histological damages and showed strong protection against DSS-induced acute colitis. Therefore, our findings suggest that compound 5e exhibits potential as a promising anti-inflammatory agent with attenuated colitis-related adverse effects.
海洋天然产物作为抗炎药物的潜在候选物仍然具有很大的潜力。在我们之前的研究中，我们成功合成了 axinelline A，这是一种天然存在的环氧化酶-2 (COX-2)抑制剂，是一种很有前途的抗炎先导化合物。本研究旨在发现具有平衡抑制作用的新型 COX 抑制剂，通过进一步对 axinelline A 的结构修饰来减轻其严重的不良反应。在合成的衍生物中，化合物 5e 表现出最高的 COX-2 抑制活性和平衡的 COX 抑制作用（IC = 1.74 μM；选择性（IC（COX-1）/IC（COX-2）= 16.32）。体外抗炎结果表明，5e 通过 NF-κB 信号通路而不是 MAPK 信号通路有效抑制了促炎介质的表达。体内溃疡性结肠炎试验表明，5e 能显著改善组织学损伤，对 DSS 诱导的急性结肠炎有很强的保护作用。因此，我们的研究结果表明，化合物 5e 具有作为一种潜在的抗炎药物的潜力，可以减轻与结肠炎相关的不良反应。
