Medicinal Chemistry and Chemical Proteomics of Ipomoeassin Natural Glycoresins

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 DESCRIPTION (provided by applicant): To date, only a very small fraction of proteins encoded by the human genome have been targeted by clinical drugs. To reduce morbidity and mortality of existing and newfound diseases, there is a fundamental need to develop new pharmaceutical agents and identify novel biological targets for therapeutic and preventative interventions. Bioactive natural products are a rich source of drug candidates and are also important tools for exploring biological systems. The ipomoeassins are a family of carbohydrate-derived macrocyclic compounds isolated from the Suriname plant Ipomoea squamosal of the morning glory family. Some members of this family are very potent inhibitors (with IC50s in the low nanomolar range) of human cancer cells. In the NCI 60-cell line screen, ipomoeassin A, the naturally most abundant member of the family, showed strong and selective growth inhibition of different cancer cells, and its pattern of activity was clearly distinguished from other known anticancer agents based on a COMPARE analysis. Therefore, it suggests that the ipomoeassins have novel molecular targets and can serve as promising new leads for drug development. The long term goal of this project is to elucidate the mechanisms by which the ipomoeassins exert their biological activities and investigate the pharmaceutical potential of this family of natural macrocycles. The objectives of this proposal are 1) to elucidate structure-activity relationships (SAR) of ipomoeassin F, and 2) to synthesize bioactive photo-crosslinking activity-based probes (hvABPs) of ipomoeassin F to identify its molecular targets. Ipomoeassin F is selected for the proposed studies because it is the most potent member of the family. Our rationale for the proposed research is that SAR evaluation and target identification are critical not only for understanding the modes of action of the ipomoeassins but also to provide essential information that will facilitate their future medical evaluation and the design of new pharmaceutical agents derived from them. Our hypothesis is that the ipomoeassins achieve their biological activities by forming complexes with a unique set of proteins in cells. A novel quantitative chemical proteomics approach is employed to test this hypothesis. In brief, the information obtained from the SAR studies will be used to design and synthesize desired chemical probes. Subsequently, specific target proteins will be captured by the probes upon UV irradiation and visualized by in-gel fluorescent imaging. The detected protein candidates will then be isolated using affinity purification and characterized by mass spectrometry. Finally, the identified protein targets will be validated using cell and molecular biology techniques. The proposed research is significant because the acquired knowledge will open the door to designing the next generation of ipomoeassin derivatives to selectively perturb functions of those target proteins for preventing and/or treating human diseases including cancer.