Design and synthesis of butyrolactone V derivatives and its anti-inflammatory activity analysis
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摘要:
目的：本研究旨在设计并合成一系列丁内酯 V 衍生物，全面评估所有衍生物的抗炎功效，探寻能够有效抑制炎症性肠病（IBD）的潜在药物，并以此确定其构效关系（SAR）。 方法：采用依次进行的氧化反应、取代反应和酯化反应，以高收率合成目标产物。在经脂多糖及所合成化合物处理的 RAW264.7 细胞中，对一氧化氮的生成量进行精确测定。随后，深入研究这些化合物在葡聚糖硫酸钠（DSS）诱导的溃疡性结肠炎模型中的活性表现。 结果：成功设计并合成了总计三个系列，涵盖 60 个天然产物丁内酯 V 的衍生物。实验结果表明，化合物 5p 和 7e 能够显著缓解 DSS 诱导的小鼠结肠炎症状，具体表现为有效减轻腹泻程度、抑制结肠长度的缩短以及降低组织损伤程度。初步的作用机制探究显示，化合物 5p 和 7e 主要通过降低趋化因子的表达水平，进而发挥抗炎作用，以此改善小鼠的 IBD 症状。 结论：本研究系统地报道了丁内酯 V 的合成、衍生化过程及其抗炎活性研究。其中，效果最为显著的化合物 5p 和 7e 具备进一步开发成为治疗 IBD 药物的潜力。
Abstract:
Objective: To design and synthesize an amount of butyrolactone V derivatives, evaluate the antiinflammatory effects of all the derivatives, look for potential drugs that inhibit inflammatory bowel disease (IBD), and determine the structure-activity relationship (SAR). Methods: The butyrolactone V derivatives were synthesized with high yield by oxidation reaction, substitution reaction, and esterification reaction in sequence, and the production of nitric oxide was assessed in RAW264.7 cells treated with the lipopolysaccharide and the compounds. Then, the target compounds were studied for their activity in dextran sodium sulfate (DSS)-induced ulcerative colitis. Results: A total of three series of compounds encompassing 60 derivatives of the natural product butyrolactone V were designed and synthesized. The results showed that compounds 5p and 7e could alleviate the symptoms of DSS-induced colitis in mice, including alleviating diarrhea, inhibiting the reduction of colon length, and reducing tissue damage. The preliminary mechanism exploration indicated that compounds 5p and 7e could improve the symptoms of IBD in mice mainly by reducing the expression of chemokines and exerting anti-inflammatory effects. Conclusion: This study reports the synthesis and the derivatization of butyrolactone V and analysis on anti-inflammatory activity. The most effective compounds 5p and 7e have the potential to be further developed as drugs to treat IBD.
关键词:
抗炎活性;丁内酯 V;炎症性肠病;天然产物;构效关系
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Project Supported:
This research was funded by the National Natural Science Foundation of China (Nos. 81725021, 81903461, and 82173705), as well as the Natural Science Foundation of Hubei Province, China (No.ZRMS2023000340). We are grateful to the Medical Subcenter of HUST Analytical & Testing Center for their assistance in data acquisition.
Wen Liu a,, Biqiong Zhang a,, Zhengxi Hu a,, Si Yao b, Yunpeng Zhao a, Fengqing Wang a, Yuanyuan Wang a, Xinxin Yang a, Jie Yin a, Weiguang Sun a, Qingyi Tong a, Lianghu Gu a,?, Yonghui Zhang a,?. Design and synthesis of butyrolactone V derivatives and its anti-inflammatory activity analysis[J]. Chinese Herbal Medicines (CHM),2026,18(1):142-152
