title: Identification and characterization of kava-derived compounds mediating TNF-alpha suppression.
abstract: There is a substantial unmet need for new classes of drugs that block TNF-alpha-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-alpha secretion in lipopolysaccharide-stimulated THP-1 cells, seeking compounds capable of interfering with the TNF-alpha-inducing transcription factor lipopolysaccharide-induced TNF-alpha 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-alpha secretion in the cell-based assay and suppressed lipopolysaccharide-induced TNF-alpha factor expression in the same cells, whereas the other compounds inhibited TNF-alpha secretion without affecting lipopolysaccharide-induced TNF-alpha factor levels, indicating a potential divergence in mechanism of action.
authors.affiliation: Department of Chemistry, Boston University, Boston, MA 02215, USA. mpollast@bu.edu
authors.forename: Michael P
authors.initials: MP
authors.lastname: Pollastri
authors.forename: Adrian
authors.initials: A
authors.lastname: Whitty
authors.forename: Jamie Cassidy
authors.initials: JC
authors.lastname: Merrill
authors.forename: Xiaoren
authors.initials: X
authors.lastname: Tang
authors.forename: Trent D
authors.initials: TD
authors.lastname: Ashton
authors.forename: Salomon
authors.initials: S
authors.lastname: Amar
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D020901:Kava / Q000737:chemistry*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D010936:Plant Extracts / Q000737:chemistry; D011753:Pyrones / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D010936:Plant Extracts; D011753:Pyrones; D014409:Tumor Necrosis Factor-alpha; C113859:dihydrokavain; C011889:kavain