The objective of this research is the discovery and chemical study of novel cyototoxic agents from higher plants. A panel of human tumor cell lines (HTLC) (A-549 (lung carcinoma), HT-29 (colon adenocarcinoma), MCF-7 (breast adenocarcinoma), RPMl-7951 (melanoma) and U251MG (glioblastoma multiforme) is utilized to measure in vitro cytotoxicity. Plants from the United States, Mexico, Brazil, Chile, Egypt, Thailand and China will be acquired for screening in the HTCL. Those plants with confirmed activities will be re-collected for large- scale bioactivity-directed fractionation. Plants that are currently under active fractionation and chemical studies include Annona coriacea, Annona muricata, Desmos cochinchinenis, Polytrichum ohioense, and Polytrichum pallidisetum. Structures of purified active compounds will be elucidated by spectroscopic and chemical methods. Current spectroscopic studies involve crystalline actives from Annona coriacea, Desmos cochinchinensis and Polytrichum ohioense. Reisolation or semi-synthesis will be carried out to provide sufficient quantities of selected active lead compounds for further evaluations in the National Cancer Institute (NCI) in vitro human tumor panel and in NCI's and Abbott Laboratories' in vivo tumor models. Two compounds (coriacin and 4- desoxycoriacin from Annona coriacea) have shown significant in vivo activity at Abbott Laboratory. Chemical studies of selected compounds will be initiated to uncover structure-activity relationships. Lead compounds for the chemical studies include the polyketides from Annonaceae, aristolactams from Pararistolochia flos-avis, and vismiones from Psorospermum febrifugum. Projects of this types have significance based on advances achieved in the investigators knowledge of natural product chemistry and the discovery of potent cytotoxic agents which may have unique mechanisms of action. In many cases these compounds find use as interesting biochemical/pharmacological probes to help elucidate basic biological processes in cells. Although the vast majority of cytotoxic agents do not find use as drugs, they do provide interesting activity leads for the development of analogs for further evaluation as potential antineoplastic agents. In addition, by evaluating these cytotoxic agents in appropriate animal tumor models, the potential exists to discover agents which may become candidates for further anticancer drug development.
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