Fermentation derived natural products from actinomycetes and other bacteria have been an important component of drug discovery inspiring 50% of clinically approved drugs and proven to be invaluable tools in cancer research. Natural products often exert their effects potently and exhibit high specificity - making them useful to probe signaling pathways related to cancer. As such, a continued effort to identify new natural products with potent biological activity relevant to human cancers is an important endeavor. The goal of this project is to identify new natural products that can be lead structures for the development of novel cancer therapeutics or biochemical probes. A multi-faceted approach that combines microbiology, natural products chemistry and collaboration with experts in cancer biology will be used to accomplish this goal. Specifically, we propose to develop new empirical and biochemical techniques to culture actinomycetes from marine habitats, by taking advantage of environmental factors such as pH, pO2 and chemical signaling. As it is widely believed that only a small percentage of bacteria are culturable, new techniques to isolate secondary metabolite producing bacteria are necessary. The collection of marine bacteria will serve as the foundation to build a natural product fraction library for biological screening efforts. We will use a combination of biochemical target-based assays, cell-based phenotypic assays and selective cytotoxicity studies to identify molecules that interact with signal transduction pathways (eg. apoptosis, necrosis, Wnt/?-catenin, HIF) and modulate epigenetic factors such as DNA methyltransferase and histone deacetylase. An example of a specific biological target, we will utilize a cell-based assay to discover molecules that interact specifically in the Wnt pathway using a Wnt responsive cell line, which is important in large number of cancers (most notably up to 90% of colon cancer). To accommodate the chemical evaluation of active hits in the large number of bioassays proposed, we will develop analytical chemistry techniques based on LC-SPE-NMR technology for rapid quantitative and qualitative analysis. Finally, we will use traditional natural products chemistry techniques to characterize new secondary metabolites that we identify in our biological screening.

Public Health Relevance

A large fraction of FDA approved anticancer drugs are based upon natural products derived from microbial resources. This research will investigate new methodologies to identify new natural products from underdeveloped resources for the treatment of cancer. Our research combines expertise in natural products along with experts in cancer biology.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA149833-02
Application #
8125064
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Fu, Yali
Project Start
2010-08-10
Project End
2015-05-31
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
2
Fiscal Year
2011
Total Cost
$319,021
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Vaden, Rachel M; Oswald, Nathaniel W; Potts, Malia B et al. (2017) FUSION-Guided Hypothesis Development Leads to the Identification of N?,N?-Dimethyladenosine, a Marine-Derived AKT Pathway Inhibitor. Mar Drugs 15:
Fu, Peng; MacMillan, John B (2017) Carpatizine, a novel bridged oxazine derivative generated by non-enzymatic reactions. Org Biomol Chem 15:5275-5278
Fu, Peng; La, Scott; MacMillan, John B (2016) 1,3-Oxazin-6-one Derivatives and Bohemamine-Type Pyrrolizidine Alkaloids from a Marine-Derived Streptomyces spinoverrucosus. J Nat Prod 79:455-62
Seitz, Tobias; Fu, Peng; Haut, Franz-Lucas et al. (2016) One-Pot Synthesis of 5-Hydroxy-4H-1,3-thiazin-4-ones: Structure Revision, Synthesis, and NMR Shift Dependence of Thiasporine A. Org Lett 18:3070-3
Colosimo, Dominic A; MacMillan, John B (2016) Detailed Mechanistic Study of the Non-enzymatic Formation of the Discoipyrrole Family of Natural Products. J Am Chem Soc 138:2383-8
Fu, Peng; Legako, Aaron; La, Scott et al. (2016) Discovery, Characterization, and Analogue Synthesis of Bohemamine Dimers Generated by Non-enzymatic Biosynthesis. Chemistry 22:3491-3495
Fisher, Kurt W; Das, Binita; Kim, Hyun Seok et al. (2015) AMPK Promotes Aberrant PGC1? Expression To Support Human Colon Tumor Cell Survival. Mol Cell Biol 35:3866-79
Potts, Malia B; McMillan, Elizabeth A; Rosales, Tracy I et al. (2015) Mode of action and pharmacogenomic biomarkers for exceptional responders to didemnin B. Nat Chem Biol 11:401-8
Fu, Peng; MacMillan, John B (2015) Thiasporines A-C, thiazine and thiazole derivatives from a marine-derived Actinomycetospora chlora. J Nat Prod 78:548-51
Fu, Peng; MacMillan, John B (2015) Spithioneines A and B, Two New Bohemamine Derivatives Possessing Ergothioneine Moiety from a Marine-Derived Streptomyces spinoverrucosus. Org Lett 17:3046-9

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