Tetrahydrocurcumin Derivatives Enhanced the Anti-Inflammatory Activity of Curcumin: Synthesis, Biological Evaluation, and Structure-Activity Relationship Analysis.

Tetrahydrocurcumin, the most abundant curcumin transformation product in biological systems, can potentially be a new alternative therapeutic agent with improved anti-inflammatory activity and higher bioavailability than curcumin. In this article, we describe the synthesis and evaluation of the anti-inflammatory activities of tetrahydrocurcumin derivatives. Eleven tetrahydrocurcumin derivatives were synthesized via Steglich esterification on both sides of the phenolic rings of tetrahydrocurcumin with the aim of improving the anti-inflammatory activity of this compound. We showed that tetrahydrocurcumin (2) inhibited TNF-α and IL-6 production but not PGE2 production. Three tetrahydrocurcumin derivatives inhibited TNF-α production, five inhibited IL-6 production, and three inhibited PGE2 production. The structure-activity relationship analysis suggested that two factors could contribute to the biological activities of these compounds: the presence or absence of planarity and their structural differences. Among the tetrahydrocurcumin derivatives, cyclic compound 13 was the most active in terms of TNF-α production, showing even better activity than tetrahydrocurcumin. Acyclic compound 11 was the most effective in terms of IL-6 production and retained the same effect as tetrahydrocurcumin. Moreover, acyclic compound 12 was the most active in terms of PGE2 production, displaying better inhibition than tetrahydrocurcumin. A 3D-QSAR analysis suggested that the anti-inflammatory activities of tetrahydrocurcumin derivatives could be increased by adding bulky groups at the ends of compounds 2, 11, and 12.

Polyphenols with Anti-Inflammatory Properties: Synthesis and Biological Activity of Novel Curcumin Derivatives.

Herein, we describe the synthesis and evaluation of anti-inflammatory activities of new curcumin derivatives. The thirteen curcumin derivatives were synthesized by Steglich esterification on one or both of the phenolic rings of curcumin with the aim of providing improved anti-inflammatory activity. Monofunctionalized compounds showed better bioactivity than the difunctionalized derivatives in terms of inhibiting IL-6 production, and known compound 2 presented the highest activity. Additionally, this compound showed strong activity against PGE2. Structure-activity relationship studies were carried out for both IL-6 and PGE2, and it was found that the activity of this series of compounds increases when a free hydroxyl group or aromatic ligands are present on the curcumin ring and a linker moiety is absent. Compound 2 remained the highest activity in modulating IL-6 production and showed strong activity against PGE2 synthesis.