Natural Products as Selective Chemotherapeutic Agents and as Chemical Probes to Understand Biological Processes



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Aware of the important role that terrestrial microbial natural products play in the discovery of therapeutics and the decrease in rate of discovery of new natural products in the pharmaceutical industry, there is an immediate need to explore novel sources of microbial natural products with biological relevance. Marine bacteria are an excellent source of bioactive metabolites. With this idea in mind our laboratory has developed new techniques to isolate >600 species of marine actinomycetes and has created a natural product fraction library from these bacterial strains. My research efforts have focused on the isolation of natural products that exhibit selective activity against a panel of tumor derived cell lines that include lung, colon, melanoma, pancreatic cancer and glioblastoma. In parallel to structure elucidation efforts of our active metabolite, the determination of its mode of action was ongoing in the laboratory of Dr. White. Through the use of a new screening tool, called FUSION (Functional Signature Ontology) we were able to determine that our active compound had similar activity to inhibitors of the TBK1 signaling pathway. Additionally, a novel polyketide was isolated from the marine-derived bacteria Salinispora arenicola, believed to be a key intermediate in the biosynthetic pathway of saliniketal, an inhibitor of ornithine decarboxylase induction. In addition, we have utilized the natural product leptomycin B (LMB), as a chemical tool to understand its inhibition of CRM1, a protein involved in export of cargo from the nucleus to the cytoplasm and a possible chemotherapeutic target. This work was done in collaboration with Dr. Chook. We observed that LMB irreversibly binds to CRM1 due to the hydrolysis of its lactone moiety causing stabilization of the protein-LMB complex. In contrast, compounds that lack the capability of being hydrolyzed by CRM1 are reversible inhibitors of CRM1. These research findings probe the question of designing molecules capable of reversibly inhibiting CRM1 and this perhaps will lead to reduced toxicity. This work illustrates the importance that natural products have not only as therapeutic agents for the treatment of diseases such as cancer but also as important chemical tools to understand complex biological processes.

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