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Identification and Characterization of Kava‐derived Compounds Mediating TNF‐ α Suppression
Author(s) -
Pollastri Michael P.,
Whitty Adrian,
Merrill Jamie Cassidy,
Tang Xiaoren,
Ashton Trent D.,
Amar Salomon
Publication year - 2009
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2009.00838.x
Subject(s) - lipopolysaccharide , tumor necrosis factor alpha , pharmacology , chemistry , in vivo , kava , biology , immunology , microbiology and biotechnology
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‐stimulated THP‐1 cells, seeking compounds capable of interfering with the TNF‐ α ‐inducing transcription factor lipopolysaccharide‐induced TNF‐ α factor. 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 lipopolysaccharide. 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 with kavain. Interestingly, a ring‐opened analog of kavain inhibited TNF‐ α secretion in the cell‐based assay and suppressed lipopolysaccharide‐induced TNF‐ α factor expression in the same cells, whereas the other compounds inhibited TNF‐ α secretion without affecting lipopolysaccharide‐induced TNF‐ α factor levels, indicating a potential divergence in mechanism of action.