Ju Zhiran, Shang Ziyi, Mahmud Taifo, Fang Jingjie, Liu Yonghong, Pan Qidong, Lin Xiuping, Chen Fener
Institute of Pharmaceutical Science and Technology, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, China.
Department of Pharmaceutical Sciences, Oregon State University, Corvallis, Oregon 97331-3507, United States.
J Nat Prod. 2023 Apr 28;86(4):958-965. doi: 10.1021/acs.jnatprod.2c01153. Epub 2023 Mar 7.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used medications to treat conditions such as arthritis, pain, and fever. They reduce inflammation by inhibiting cyclooxygenase (COX) enzymes that catalyze the committed step in prostaglandin (PG) biosynthesis. Despite their significant therapeutic benefits, many NSAIDS have undesirable adverse effects. The aim of this study was to discover novel COX inhibitors from natural sources. Here, we describe the synthesis and anti-inflammatory activity of the COX-2 inhibitor axinelline A (), which was isolated from SCSIO02208, and its analogues. Compared to the synthetic analogues, the natural product has stronger COX inhibitory activity. Although is more active against COX-2 than COX-1, its selectivity index is low; therefore, it may be classified as a nonselective COX inhibitor. Its overall activity is comparable to the clinically used drug diclofenac. studies showed that binds to COX-2 in a similar manner to diclofenac. Inhibition of COX enzymes by in LPS-stimulated murine RAW264.7 macrophages resulted in suppression of the NF-κB signaling pathway, leading to reduced expression of pro-inflammatory factors such as iNOS, COX-2, TNF-α, IL-6, and IL-1β and reduced production of PGE, NO, and ROS. The potent anti-inflammatory activity of , together with its lack of cytotoxicity, makes it an attractive candidate for a new anti-inflammatory lead.
非甾体抗炎药（NSAIDs）是广泛用于治疗关节炎、疼痛和发热等病症的药物。它们通过抑制环氧化酶（COX）来减少炎症，COX催化前列腺素（PG）生物合成中的关键步骤。尽管它们具有显著的治疗益处，但许多NSAIDs有不良副作用。本研究的目的是从天然来源发现新型COX抑制剂。在此，我们描述了从SCSIO02208中分离出的COX-2抑制剂轴海绵素A（）及其类似物的合成和抗炎活性。与合成类似物相比，天然产物具有更强的COX抑制活性。虽然对COX-2的活性比对COX-1更强，但其选择性指数较低；因此，它可被归类为非选择性COX抑制剂。其总体活性与临床使用的药物双氯芬酸相当。研究表明，与双氯芬酸以相似的方式与COX-2结合。在脂多糖刺激的小鼠RAW264.7巨噬细胞中，对COX酶的抑制导致NF-κB信号通路的抑制，从而导致促炎因子如诱导型一氧化氮合酶、COX-2、肿瘤坏死因子-α、白细胞介素-6和白细胞介素-1β的表达降低，以及前列腺素E、一氧化氮和活性氧的产生减少。轴海绵素A强大的抗炎活性及其缺乏细胞毒性，使其成为一种有吸引力的新型抗炎先导化合物候选物。
