The primary focus of this project is the isolation and characterization of new chemotypes for the treatment of infectious diseases. This includes research involving the development of instrumentation for the rapid and thorough analysis of bioactive organic compounds in complex biological mixtures. Our goal is to integrate the most powerful tools available for the purification and structure determination of organic materials into a single system while being able to recover nearly 95 percent of the purified sample for biological evaluation. The most promising metabolites will be studied for structure-activity relationships (SAR) using semi-synthesis, microbial transformations and molecular modeling. Natural product research during the last few decades has yielded thousands of novel organic compounds from the marine environment. The bioassays guiding these isolations typically have been antimicrobial, antitumor, antiviral or antiinflammatory. Little has been done to explore the oceans for compounds with activity against HIV, AIDS OI, TB and other infectious diseases. Additionally, because of the limits associated with the conventional self-contained underwater breathing apparatus (SCUBA), the majority of the compounds characterized from the marine environment are the results of shallow water collections (-30m). Dr. Michael Boyd, of the Laboratory of Drug Discovery Research and Development at the National Cancer Institute indicates that mass screening has proved to be the most effective means of discovering entirely new chemotypes not even suspected to have relevant biochemical properties. The objective of this proposed research program is to collect and screen marine samples for possible treatments of HIV and AIDS OI from depths and locations in the ocean which have remained unexplored. The active component(s) of those extracts showing promising activity will be isolated using preparative and semi-preparative high pressure liquid chromatography (HPLC) interfaced with NMR and FTMS. The chemical structures of the biologically active secondary metabolites will be determined with the use of LC-NMR-FTMS and 2D NMR. Methods for providing sufficient quantities for in vivo testing via synthesis, semi-synthesis or reisolation will be addressed for promising compounds. SAR studies will be conducted utilizing chemical and microbial transformations of biologically active secondary metabolites combined with molecular modeling studies.
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