DIVERSE NATURAL PRODUCTS FROM ISOLATION AND CHEMICAL MODIFICATION

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Cancer can be considered a disease of altered intercellular signalling. The goal of these studies is to identify and develop novel natural product inhibitors of oncogene signalling pathways for the effective treatment and prevention of cancer. The signalling targets which will be used include enzymes of phospholipid signaliing (phosphatidylinositol phospholipase C, phosphatidylinositol-3-kinase and phospholipase D), protein serine/threonine kinases (Raf-1 kinase, MEK kinase and MAP- kinase) and enzymes that regulate the cell Cycle (cdc26 phosphatase and cdk4 kinase). The sources of the natural products will be plants used in traditional Chinese medicine, native Americans' medicinal plants, fungal extracts, and combinatorial libraries of natural product derived molecules ("progenomers"). Identified collaborators in China will provide, via Hong Kong, plants which cover the major habitats of herbal growth in China. Readily available natural products with interesting biological activities, will be used as "biological scaffolds" to prepare diverse mixtures of products ("progenomers") by use of non-selective reagents, reaction and/or reaction conditions. Active leads will be identified by bioassay-directed fingerprinting using high performance liquid chromatography to obtain for each crude extract or mixture of "progenomers", fractions in 96 well microtiter plates, which will be submitted for screening. Fingerprints of each of these fractions will be available in the form of ultraviolet/visible spectra collected by a diode array detector and stored in a data bank. On identification of active fractions, the original reference plate will be retrieved and mass spectra and NMR and other spectral data will be collected on the active wells to complete the fingerprinting. This fingerprint will be used to recollect the desired material for further purification and testing Structure elucidation will be done by state of the art methods in organic chemistry. Compounds of analogous structures to those found to be active will be obtained by synthesis or from other sources, where practical, and screened. The pure compounds exhibiting activity in the biochemical target screens will be evaluated for growth inhibitory activity against tumor cells in vitro and those compounds of sufficient in vitro activity will be further evaluated in vivo. Preclinical development of promising lead compounds will be carried out by our commercial collaborator.