The strategy of this proposal is to develop and use innovative approaches, based on new understanding of tumor biology and the molecular understanding of cancer, to discover chemotherapeutics effective in treating solid tumors of the breast, prostate, ovary, lung and colon. The goal of this laboratory program of our NCNPDDG project will be to use these assays to discover new lead compounds from field collected marine cyanobacteria and macroalgae as well as cultured marine microalgae. The long term objective of this research is to use innovative biochemical and cell-based assays to discover and describe structurally-novel natural products as anticancer lead compounds from marine macroalgae and microalgae.
The specific aims of this work are to: 1) to evaluate approximately 1000- 1200 extracts of various field collected or cultured marine micro- and macro-algae over a 5 year period in a series of innovative biochemical and cell-based assays available at Sandoz Pharmaceutical, 2) to fractionate active extracts from the above screening efforts, following activity with either the biochemical or cell-based assays, as appropriate, to obtain pure natural products which are potential anticancer leads, 3) to elucidate the structures of pure active compounds using spectrochemical techniques, 4) to continue the scaled-up culture of active species or re-collection of tuft-forming or macroalgal species and re-isolation of active compounds to provide samples for pharmacologic and clinical investigation, 5) to produce semi-synthetic analogs of active compounds for exploration of structure-activity relationships in new lead compounds, and 6) to obtain patent coverage on promising antitumor natural products and their derivatives. The methodologies for collection of marine microalgae from the tropics and macroalgae from the tropics as Well as temperate locations will use shallow water field collection techniques in use in our laboratory. Aqueous and lipid extracts will be evaluated in innovative biochemical and cell based assays with our collaborators at Sandoz. Isolation of the active compounds will be followed with the biochemical assays, and a palate of spectrochemical methods emphasizing two-dimensional nuclear magnetic resonance will be used to solve the structures of the new anticancer lead compounds. Recollections or recultures will provide samples of new cancer lead compounds for in-depth biochemical and in vivo evaluations.
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