isolation, structure elucidation and synthesis of biologically active marine natural products

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The objective of the proposed research will be to discover structurally novel marine natural products that can be used as chemical tools in cell biology and whole animal investigations of autophagy, miRNA gene silencing, and toll-like-receptor-5 (TLR5) signaling. Organic synthesis will be used to investigate the SAR of the new pharmacophores, to make biotinylated probes for protein target identification, and provide sufficient material for animal studies. A 'Forward Chemical Genetics' approach that employs cell-based assays to screen chemical libraries for non-toxic small molecule modulators of gene product (protein) function that produce phenotypes of interest will be used to facilitate the discovery of new marine natural product cell biology tools. The biological systems, autophagy, miRNA gene silencing, and toll-like-receptor-5 signaling, have been chosen because: i) they have recently been recognized to play important roles in basic cell biology and human disease (neurodegeneration and cystic fibrosis), ii) all three are incompletely characterized at the genetic and protein level, and iii) there are no small molecule modulators known for two of them and only non-selective modulators available for the third. Marine invertebrates and microorganisms from tropical habitats in Papua New Guinea, Indonesia, and Dominica and from cold water habitats in BC will serve as a rich and relatively unexplored resource of novel chemical diversity for this marine natural products discovery/chemical genetics research. The research will provide new molecular tools to study important biological processes at the genetic and protein level in single cells and animals, help identify new drug targets, and may provide lead compounds for development of drugs for the treatment of neurodegeneration and cystic fibrosis. Discovery of new bioactive natural products adds unique diversity to the pool of known chemical entities, reveals unknown biosynthetic pathways and pharmacophores, and provides attractive targets for synthetic organic chemists, stimulating the development of new synthetic strategies and methodology.