Structure–Activity Relationship of Curcumin: Role of the Methoxy Group in Anti-inflammatory and Anticolitis Effects of Curcumin

Abstract

Curcumin, a dietary compound from turmeric, has beneficial effects on inflammatory diseases such as inflammatory bowel disease. Most previous studies have focused on the structure-activity relationship of the thiol-reactive α,β-unsaturated carbonyl groups of curcumin, so little is known about the roles of methoxy groups in biological activities of curcumin. Here we synthesized a series of curcumin analogues with different substitution groups (R = H-, Br-, Cl-, F-, NO₂-, CH₃-, and OH-) to replace the methoxy group and evaluated their biological effects in vitro and in vivo. Curcumin, Cur-OH, and Cur-Br (25 μM) suppressed 74.91 ± 0.88, 77.75 ± 0.89, and 71.75 ± 0.90% of LPS-induced NO production, respectively (P < 0.05). Similarly, these compounds also decreased iNOS expression, COX-2 expression, and NF-κB signaling in RAW 264.7 macrophage cells (P < 0.05). However, other analogues, especially Cur-NO₂, were inactive (P > 0.05). In the dextran sulfate sodium (DSS)-induced colitis mouse model, the Cur-Br analogue also showed a beneficial effect the same as curcumin (P < 0.05), whereas the Cur-NO₂ analogue had no effect in the animal model (P > 0.05). Together, the analogues have dramatically different effects on inflammation, supporting that the substitution group on the methoxy position plays an important role in the anti-inflammatory effects of curcumin. The methoxy group is a potential structural candidate for modification to design curcumin-based drugs for inflammatory diseases.