Identification and characterization of Kava-derived compounds mediating TNF-alpha suppression
There is a substantial unmet need for new classes of drugs that block TNF-α-mediated inflammation, and particularly for small molecule agents that can be taken orally. We have screened a library of natural products against an assay measuring TNF-α secretion in lipopolysaccharide (LPS)-stimulated THP-1 cells, seeking compounds capable of interfering with the TNF-α inducing transcription factor Lipopolysaccharide Induced TNF Alpha Factor (LITAF). Among the active compounds were several produced by the kava plant (Piper mysticum), extracts of which have previously been linked to a range of therapeutic effects. When tested in vivo, a representative of these compounds, kavain, was found to render mice immune to lethal doses of LPS. Kavain displays promising pharmaceutical properties, including good solubility and high cell permeability, but pharmacokinetic experiments in mice showed relatively rapid clearance. A small set of kavain analogs was synthesized, resulting in compounds of similar or greater potency in vitro compared to kavain. Interestingly, a ring-opened analog of kavain inhibited TNF-α secretion in the cell based assay and suppressed LITAF expression in the same cells, whereas the other compounds inhibited TNF-α secretion without affecting LITAF levels, indicating a potential divergence in mechanism of action.
TNF-α, TNF-alpha, inflammation, kava root extract, kavain, medicinal chemistry, optimization, LITAF
Tumor necrosis factor - Antagonists, Kava plant
Natural Products Chemistry and Pharmacognosy | Pharmaceutics and Drug Design
John Wiley & Sons A/S
Pollastri, Michael P.; Whitty, Adrian; Merrill, Jamie Cassidy; Ashton, Trent D.; and Amar, Salomon, "Identification and characterization of Kava-derived compounds mediating TNF-α suppression" (2009). Chemistry and Chemical Biology Faculty Publications. Paper 2. http://hdl.handle.net/2047/d20002075
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