Synthesis and anti-inflammatory properties of glycosylated cinnamaldehyde derivatives in mice models of colitis and gout

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.