The major objectives of Program 2 of this overall research program are to prepare extracts of all collected plant materials for initial biological testing and to isolate and structurally characterize novel anti-neoplastic agents from plants. Species collected in the field will be received from Program 1 (University of Illinois at Chicago), and a non-polar (organic solvent-soluble) extract will be prepared for each sample. Weighed amounts of each non-polar extract will be distributed to Programs 3 (University of Illinois at Chicago), 4 (Research Triangle Institute), and 5 (Bristol-Myers Squibb) for initial biological evaluation, with the residual extracts to be stored in a frozen repository in case of later need. Dereplication of known active compounds will be performed by a HPLC/ESMS/UV/database procedure, coupled with a consideration of prior scientific literature. The active principle(s) of each recollected, satisfactorily dereplicated, confirmed-active plant part made available by Program 1 will be isolated by a combination of standard solvent partition and chromatographic procedures, using one of the various bioassays developed by the consortium to guide the fractionation. Such bioassays will include mechanism-based screens covering a broad range of targets implicated in cancer cell growth and metastasis as well as more traditional cellular cytotoxic methods. Spectroscopic, chemical, and molecular modeling methods will be used to determine the structures of pure active isolates. Particular emphasis will be given to modern one- and two- dimensional nuclear magnetic resonance techniques for compound structure elucidation. Compounds representing a new carbon skeleton or presenting unusually difficult structural problems will be submitted for single-crystal X-ray crystallographic analysis to Program 5 (Bristol- Myers Squibb). To permit more advanced biological testing to be performed and also to aid in analog development studies, active compounds will be re-isolated in large quantities, when deemed appropriated by the consortial group. It is anticipated that the overall outcome of Program 2 will be discovery of one or more selectively active natural products that show promise for future development as cancer chemotherapeutic agents.
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