The overarching goal of this Program Project proposal is to discover naturally products from diverse natural sources that can serve as anticancer drug leads. Project 2, located at the College of Pharmacy, University of Illinois at Chicago (UIC), is comprised of botanical, chemical and biological elements. The primary goals for Project 2 are the discovery of new lead anticancer compound candidates from cyanobacteria and providing tropical plant material for Project 1, housed at The Ohio State University (OSU). The underlying hypothesis for Project 2 is that the diverse natural product structures from cultured non-marine cyanobacteria and tropical plants will be a rich source for anticancer leads. To achieve the stated goals the specific aims for Project 2 are as follows: 1) to obtain, culture, extract, and prepare fractions of cyanobacterial strains. We will obtain 100 non-marine cyanobacterial strains per year. The strain collection will focus on samples collected in the continental U.S. Each strain will be cultured, extracted and prefractionated. The resulting fractions (-700 fractions/year) will be submitted for biological evaluation in the biological test systems available at Core A, Projects 1 and 3 as well as our pharmaceutical partner, Eisai. 2) to isolate and determine the structures of the active cyanobacterial metabolites. Fractions showing promising activity in the biological test systems will be analyzed by LC-MS-NMR to identify any known active compounds (dereplication). Active fractions expected to contain novel metabolites will be fractionated using assay guided fractionation to obtain pure natural product(s). Isolates will be structurally defined using microscale NMR and MS methodologies. Structurally-characterized compounds will be submitted for extensive evaluation in the biological test systems available in Core A, Projects 1 and 3 as well as our pharmaceutical partner, Eisai Research institute. In addition. Core B will perform chemical optimization and modifications of prioritized compounds. We will re-isolate larger amounts of any candidate compounds for further evaluation. 3) To acquire all plant materials that will be required by the proposed Program Project We will provide 300 fully documented plant samples per year to Project 1 for extraction and biologica evaluation. We will also re-collect plant materials for larger scale isolation, as needed.
; The primary purpose of Project 2 of this program project is to discover new cancer chemotherapeutic leads from cyanobacteria and to supply plants from tropical rainforests for further investigation in Project 1. The proposed research will impact human health by creating new lead compounds for the development of drugs to treat cancer. Some of the compounds discovered may work by new mechanism of action, thus increasing our understanding how to treat this disease.
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