Discovery and evaluation of asymmetrical monocarbonyl analogs of curcumin as anti-inflammatory agents

Abstract

Sepsis is a systemic inflammatory response syndrome and is mainly caused by lipopolysaccharides (LPS) – a component of the cell walls of gram-negative bacteria, via toll-like receptor 4–mitogen-activated protein kinases/nuclear factor-kappa B-dependent proinflammatory signaling pathway. Here, we synthesized 26 asymmetric monocarbonyl analogs of curcumin and evaluated their anti-inflammatory activity by inhibiting the LPS-induced secretion of tumor necrosis factor-α and interleukin-6 in mouse RAW264.7 macrophages. Five active compounds (3a, 3c, 3d, 3j, and 3l) exhibited dose-dependent inhibition against the release of tumor necrosis factor-α and interleukin-6, and they also showed much higher chemical stability than curcumin in vitro. The anti-inflammatory activity of analogs 3a and 3c may be associated with their inhibition of the phosphorylation of extracellular signal-regulated kinase and the activation of nuclear factor-kappa B. In addition, 3c exhibited significant protection against LPS-induced septic death in vivo. These results indicate that asymmetrical monocarbonyl curcumin analogs may be utilized as candidates for the treatment of acute inflammatory diseases.

Keywords:

• sepsis
• inflammatory cytokines
• anti-inflammation
• quantitative structure–activity relationship

Acknowledgments

Financial support was provided by the National Natural Science Funding of China (Grants 21272179 and 81202462), High-Level Innovative Talent Funding of Zhejiang Department of Health (GL), Zhejiang Natural Science Funding (Grant LQ12H30002), Grant from the Zhejiang Department of Health (2012KYA129), the Zhejiang Zhejiang Key Group Project in Scientific Innovation (2010R50042), and the Research Development Fund of Wenzhou Medical University (QTJ13003). The project was sponsored by the China Postdoctoral Science Foundation (grants 20090461121 and 201003591).

Disclosure

The authors report no conflicts of interest in this work.