Inhibition of LPS-induced production of inflammatory factors in the macrophages by mono-carbonyl analogues of curcumin.
ABSTRACT Curcumin (diferuloylmethane) is an orange-yellow compound from turmeric (Curcuma longa), a spice found in curry powder. Traditionally known for its anti-inflammatory effects, curcumin has established itself in the last two decades to be a potent immunomodulatory agent that can regulate the activation of a variety of immunocytes and the expression of inflammatory factors. Considering that the beta-diketone moiety of curcumin may result in its instability and poor metabolic property, we previously designed a series of mono-carbonyl analogues of curcumin with enhanced stability by deleting this moiety. These compounds demonstrate improved pharmacokinetic profiles both in vitro and in vivo. In this study, we reported a total of 44 mono-carbonyl analogues, which have been evaluated for the inhibitory activities against LPS-induced TNF-alpha and IL-6 release in the macrophages. Based on the screening results of these analogues, five active compounds A01, A03, A13, B18 and C22 were investigated to inhibit TNF-alpha and IL-6 release in a dose-dependent manner, three of which further demonstrated inhibitory effects on LPS-induced TNF-alpha, IL-1beta, IL-6, MCP-1, COX-2, PGES, iNOS and p65 NF-kappaB mRNA production. The results indicated that these mono-carbonyl analogues may possess anti-inflammatory activities similar to curcumin despite the absence of the beta-diketone. These mono-carbonyl analogues may be a favourable alternative for the development of curcumin-based anti-inflammatory drugs both pharmacokinetically and pharmacologically. We further examined the biological properties of A13, the only hydrosoluble analogue when combined with hydrochloric acid. The results showed a dose-dependent inhibition of LPS-induced cytokine production. These data further indicated that compound A13 may be explored as a promising anti-inflammatory molecule.