Based on continuing success and promising results in the previous grant period, the overall goal of the proposed research is to discover novel anticancer drugs from selected medicinal plants that have been chosen either for their therapeutic use to treat cancer(s) or for their novelty. Lead compounds will be isolated and identified based on cytotoxicity (human tissue culture cell line panel), mechanistic (DNA topoisomerase assays), and molecular target-based screening (androgen/androgen receptor target based assays). The identification and development of clinical trial candidates are overall goals of our program. The following specific studies will be carried out to accomplish these goals: 1) The Natural Products Laboratory (NPL) will use analytical instrumental chromatography to isolate and identify the active principles found in anticancer bioassays) termed bioactivity-directed fractionation and isolation, BDFI). The structural characterization of new active leads will be carried out by physical and spectral techniques. 2) Certain leads will be selected for structural modification and synthesis of analogs in order to elucidate their structure-activity relationships and mechanism of action as well as to improve their pharmacological profiles. Conventional structure activity relationship (SAR) studies, molecular modeling approaches, and combinatorial chemistry techniques are used by the NPL to aid lead generation and optimization. Current classes of primary interest include fluorinated phenyl quinolones, dithiophene and epipodophyllotoxin-camptothecin conjugates. 3) Promising compounds and their synthetic analogs will be submitted to the National Institutes of Health (NIH) at the National Cancer Institute (NCI) for additional in vitro and in vivo antitumor studies. Our previous program has been augmented by participation in the NCI Natural Product Repository Program (NCI-NPRP) for the study of promising cytotoxic rainforest species, and by the collaboration of Dr. C. S. Chang, University of Rochester Medical School, who has unique expertise in screening for prostate cancer targets. Our program continues to have the advantages of 1) an excellent supply of highly active lead compounds, (2) a focus on the structural modification of these new leads as clinical trials candidates, and (3) excellent productivity and a superior prospect for the successful development of a clinically useful drugs.
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