The overarching goal of this project is to discover new natural products with anticancer applications from marine cyanobacteria and algae using mechanism-based assays against epigenetic targets. Tropical shallow water benthic cyanobacteria and algae have been rich taxonomic groups for the production of medicinally-relevant natural products. However, the majority of the ocean's cyanobacteria and many macroalgae have been little sampled and largely overlooked in previous anticancer drug discovery programs, mainly because most species attain little biomass under natural conditions. One important and underlying hypothesis being examined in this proposed work is that marine cyanobacteria belonging to many genera other than those studied to date will also be rich in their production of anticancer-type natural products.
The specific aims which lead to this long term goal are: 1. To access previously unstudied marine cyanobacteria and macroalgae through examination of new habitats and new strategies for their collection and culture 2. To apply improved and innovative paradigms to enhance the detection of bioactive compounds from cyanobacterial/macroalgal extracts, including prefractionation and pure compound library formation 3. To screen marine cyanobacterial and algal derived compounds and reduced complexity mixtures for anticancer-type activities at Novartis (NIBR) using contemporary mechanism-based screening against epigenetic targets 4. To derepticate nuisance compounds through application of combined LC-MS and Microcoil NMR profiling procedures 5. To isolate and structurally define cyanobacterial and algal metabolites that are active in the NIBR mechanism-based assays using HPLC followed by efficient NMR and MS methodologies 6. To scale-up the isolation of active compounds to assist NIBR drug development efforts using recollection, culture, genetic-based methods, or synthetic/semi-synthetic methods, as appropriate and efficient 7. To patent notable discoveries and publish all results in the peer-reviewed literature.
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