Wong Wei-Ting, Li Lan-Hui, Chiu Hsiao-Wen, Chiang Po-Yu, Lu Hsueh-Chen, Wu Chun-Hsien, Ho Chen-Lung, Lo Lee-Chiang, Hua Kuo-Feng
Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan.
Department of Laboratory Medicine, Linsen, Chinese Medicine and Kunming Branch, Taipei City Hospital, Taipei, Taiwan.
Biomed Pharmacother. 2025 Sep;190:118441. doi: 10.1016/j.biopha.2025.118441. Epub 2025 Aug 9.
Cinnamaldehyde, a natural compound with diverse biological activities, has limited biomedical application due to its potential cytotoxicity. In this study, we synthesized a series of novel glycosylated cinnamaldehyde derivatives by varying both the sugar moiety and its attachment position on the aromatic ring. Preliminary screening for cytotoxicity and anti-inflammatory activity revealed that these structural modifications critically influenced bioactivity. Among the derivatives, compound 1a, bearing a β-D-galactosyl group at the para-position of the cinnamaldehyde phenyl ring, exhibited the most promising therapeutic potential. In contrast, replacing the β-D-galactosyl group with β-D-glucosyl (1b) or α-D-mannosyl (1c) residues resulted in loss of anti-inflammatory activity. Similarly, shifting the β-D-galactosyl group to the meta (1d) or ortho (1e) positions also abolished activity, highlighting the importance of both sugar identity and its positional attachment in determining function. Subsequent mechanistic studies focused on compound 1a and its effect on the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, a central mediator in inflammatory disorders. Compound 1a effectively suppressed NLRP3 inflammasome activation by reducing mitochondrial damage and disrupting inflammasome complex assembly in macrophages. Furthermore, 1a promoted Sirt1-mediated autophagy, which contributed to additional inhibition of inflammasome activation. Notably, 1a inhibited not only the NLRP3 inflammasome but also the NLRC4 inflammasome in macrophages. In vivo, oral administration of 1a significantly alleviated both dextran sulfate sodium (DSS)-induced colitis and monosodium urate (MSU)-induced peritonitis in mice, primarily through NLRP3 inflammasome suppression. Collectively, these findings identify compound 1a as a promising lead compound for the treatment of inflammasome-driven inflammatory diseases and underscore the therapeutic potential of rational glycosylation-based modification of cinnamaldehyde.
肉桂醛是一种具有多种生物活性的天然化合物，但由于其潜在的细胞毒性，其生物医学应用受到限制。在本研究中，我们通过改变糖部分及其在芳香环上的连接位置，合成了一系列新型糖基化肉桂醛衍生物。细胞毒性和抗炎活性的初步筛选表明，这些结构修饰对生物活性有至关重要的影响。在这些衍生物中，化合物1a在肉桂醛苯环的对位带有β-D-半乳糖基，表现出最有前景的治疗潜力。相比之下，用β-D-葡萄糖基（1b）或α-D-甘露糖基（1c）残基取代β-D-半乳糖基会导致抗炎活性丧失。同样，将β-D-半乳糖基转移到间位（1d）或邻位（1e）也会消除活性，突出了糖的身份及其位置连接在决定功能方面的重要性。随后的机制研究集中在化合物1a及其对含NOD、LRR和pyrin结构域的蛋白3（NLRP3）炎性小体的影响上，NLRP3炎性小体是炎症性疾病的核心介质。化合物1a通过减少线粒体损伤和破坏巨噬细胞中炎性小体复合物的组装，有效抑制了NLRP3炎性小体的激活。此外，1a促进了Sirt1介导的自噬，这有助于进一步抑制炎性小体的激活。值得注意的是，1a不仅抑制巨噬细胞中的NLRP3炎性小体，还抑制NLRC4炎性小体。在体内，口服1a可显著减轻葡聚糖硫酸钠（DSS）诱导的小鼠结肠炎和尿酸钠（MSU）诱导的腹膜炎，主要是通过抑制NLRP3炎性小体实现的。总的来说，这些发现确定化合物1a是治疗炎性小体驱动的炎症性疾病的有前景的先导化合物，并强调了基于合理糖基化修饰肉桂醛的治疗潜力。
