College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea.
College of Pharmacy, Kyunghee University, Seoul, 02447, Republic of Korea.
Eur J Med Chem. 2019 Oct 15;180:86-98. doi: 10.1016/j.ejmech.2019.07.016. Epub 2019 Jul 6.
The aim of this study was to design and synthesize COX-1/COX-2 balanced inhibitors incorporating the structural motifs of anti-inflammatory ascidian metabolites. We designed a series of substituted indole analogs that incorporate the key structures of the ascidian metabolites, herdmanines C and D. The synthesized analogs were tested for their inhibitory activity against COX-1 and COX-2, and compound 5m, which displayed balanced inhibition, was further evaluated for in vitro anti-inflammatory activity. Compound 5m suppressed the expression of pro-inflammatory factors, including iNOS, COX-2, TNF-α, and IL-6 in LPS-stimulated murine RAW264.7 macrophages. The reduction of PGE, NO, and ROS was also observed, together with the suppression of NF-κB, IKK, and IκBα phosphorylation. Our results characterized 5m as a COX-1/COX-2 balanced inhibitor that subsequently caused ROS inhibition and NF-κB suppression, and culminated in the suppression of iNOS, COX-2, TNF-α, and IL-6 expression.
本研究旨在设计和合成 COX-1/COX-2 平衡抑制剂，将抗炎海洋生物活性物质 herdmanines C 和 D 的结构母核纳入其中。我们设计了一系列取代的吲哚类似物，其中包含海洋生物活性物质 herdmanines C 和 D 的关键结构。合成的类似物被测试对 COX-1 和 COX-2 的抑制活性，化合物 5m 表现出平衡抑制作用，进一步评估其体外抗炎活性。化合物 5m 抑制 LPS 刺激的鼠 RAW264.7 巨噬细胞中促炎因子的表达，包括 iNOS、COX-2、TNF-α 和 IL-6。还观察到 PGE、NO 和 ROS 的减少，以及 NF-κB、IKK 和 IκBα 磷酸化的抑制。我们的研究结果表明 5m 是一种 COX-1/COX-2 平衡抑制剂，随后抑制 ROS 和 NF-κB，从而抑制 iNOS、COX-2、TNF-α 和 IL-6 的表达。
