Identification and characterization of Kava-derived compounds mediating TNF-alpha suppression Pollastri, Michael P., Whitty, Adrian, Merrill, Jamie Cassidy, Tang, Xiaoren, Ashton, Trent D. and Amar, Salomon 2009, Identification and characterization of Kava-derived compounds mediating TNF-alpha suppression, Chemical biology and drug design, vol. 74, no. 2, pp. 121-128, doi: 10.1111/j.1747-0285.2009.00838.x. Attached Files Name Description MIMEType Size Downloads Title Identification and characterization of Kava-derived compounds mediating TNF-alpha suppression Author(s) Pollastri, Michael P. Whitty, Adrian Merrill, Jamie Cassidy Tang, Xiaoren Ashton, Trent D. orcid.org/0000-0002-6707-6064 Amar, Salomon Journal name Chemical biology and drug design Volume number 74 Issue number 2 Start page 121 End page 128 Total pages 8 Publisher Wiley-Blackwell Publishing Place of publication Malden, Mass. Publication date 2009-08 ISSN 1747-0277 1747-0285 Keyword(s) inflammation TNF-a optimization medicinal chemistry LITAF kavain kava root extract Summary 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. Language eng DOI 10.1111/j.1747-0285.2009.00838.x Field of Research 030401 Biologically Active Molecules Socio Economic Objective 970103 Expanding Knowledge in the Chemical Sciences HERDC Research category C1.1 Refereed article in a scholarly journal Copyright notice ©2009, John Wiley & Sons A/S Persistent URL http://hdl.handle.net/10536/DRO/DU:30039282 Document type: Journal Article Collections: Faculty of Science, Engineering and Built Environment School of Life and Environmental Sciences Related Links Link Description Connect to published version (restricted access) Go to link with your DU access privileges     Unless expressly stated otherwise, the copyright for items in DRO is owned by the author, with all rights reserved. Versions Version Filter Type Mon, 24 Oct 2011, 14:15:52 EST Wed, 26 Oct 2011, 14:16:28 EST Wed, 26 Oct 2011, 14:21:32 EST Wed, 26 Oct 2011, 14:23:14 EST Wed, 02 Nov 2011, 08:04:07 EST Thu, 02 Feb 2012, 08:10:46 EST Mon, 20 Feb 2012, 09:16:14 EST Thu, 11 Dec 2014, 17:22:34 EST Filtered Full Citation counts:   Cited 21 times in TR Web of Science Cited 23 times in Scopus Search Google Scholar Access Statistics: 401 Abstract Views, 2 File Downloads  -  Detailed Statistics Created: Mon, 24 Oct 2011, 14:15:52 EST