Zhou Ying, Du Zhiteng, Wu Qianqian, Guo Mi, Chen Zhichao, Sun Chenhui, Li Xiaobo, Zou Yu, Zheng Zhiwei, Chen Pan, Cho Won-Jea, Cho Young-Chang, Chattipakorn Nipon, Wang Yi, Liang Guang, Tang Qidong
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China; College of Pharmacy, Chonnam National University, Gwangju, 61186, South Korea.
Eur J Med Chem. 2024 Mar 15;268:116252. doi: 10.1016/j.ejmech.2024.116252. Epub 2024 Feb 22.
The modification based on natural products is a practical way to find anti-inflammatory drugs. In this study, 26 osthole derivatives were synthesized, and their anti-inflammatory properties were evaluated. The preliminary activity study revealed that most osthole derivatives could effectively inhibit inflammatory cytokines IL-6 secretion in LPS stimulated mouse macrophages J774A.1. Compound 7m exhibited the most effective anti-inflammatory activity (RAW264.7 IL-6 IC: 4.57 μM, 32 times more active than osthole) in vitro with no significant influence on cell proliferation. Additionally, the mechanistic analysis demonstrated that compound 7m could block MAPK signal transduction by inhibiting the phosphorylation of JNK and p38, thereby inhibiting the release of inflammatory cytokines. Moreover, in vivo functional investigations revealed that 7m could substantially reduce DSS-induced ulcerative colitis and LPS-induced acute lung injury, with good therapeutic effects. The pharmacokinetics and acute toxicity experiments proved the safety and reliability of 7min vivo. Overall, Compound 7m could further be studied as potential anti-inflammatory candidate.
基于天然产物的修饰是寻找抗炎药物的一种实用方法。在本研究中，合成了26种蛇床子素衍生物，并对其抗炎特性进行了评估。初步活性研究表明，大多数蛇床子素衍生物能够有效抑制脂多糖刺激的小鼠巨噬细胞J774A.1中炎性细胞因子IL-6的分泌。化合物7m在体外表现出最有效的抗炎活性（RAW264.7 IL-6 IC：4.57 μM，活性是蛇床子素的32倍），且对细胞增殖无显著影响。此外，机制分析表明，化合物7m可通过抑制JNK和p38的磷酸化来阻断MAPK信号转导，从而抑制炎性细胞因子的释放。此外，体内功能研究表明，7m可显著减轻右旋糖酐硫酸钠诱导的溃疡性结肠炎和脂多糖诱导的急性肺损伤，具有良好的治疗效果。药代动力学和急性毒性实验证明了7m在体内的安全性和可靠性。总体而言，化合物7m可作为潜在的抗炎候选物进一步研究。
