This project is aimed at the ultimate goal of providing new therapeutic agents for the treatment of cancer. It involves the preparation and biological evaluation of libraries of heterocyclic compounds designed on the basis of a potent anticancer natural product podophyllotoxin. Although the clinical trials utilizing podophyllotoxin have been disappointing due to the severe gastrointestinal toxicity of the natural compound, the use of this agent as a lead in anticancer drug design has resulted in such useful cancer fighting drugs as etoposide, teniposide and etoposide phosphate. These successes fuel further research efforts in this area directed at preparation of analogues, which are expected to have improved potency and reduced toxicity. Unfortunately, the complex chemical structure of podophyllotoxin virtually prevents the generation of such libraries of analogues from simple commercially available materials and, therefore, podophyllotoxin itself is normally utilized as a starting material in these projects. Such approaches are, however, limited by the type of chemistry that podophyllotoxin can undergo and many designed analogues are synthetically inaccessible from the parent natural product. We have discovered a library of heterocyclic analogues of podophyllotoxin, which come close to the natural compound in terms of their cytotoxic potency and can be prepared utilizing a one-step synthesis from commercially available starting materials. In the proposed research project we aim to (1) significantly extend the structure-activity relationship data by systematically varying all portions of the structural scaffold of these compounds, (2) gain a detailed understanding of the mode of action underlying the anticancer activity of these compounds, and (3) identify lead compounds suitable for animal testing and further development as anticancer agents. Furthermore, the synthetic chemistry aspect of the proposed work is expected to result in discoveries of fundamental significance. This new knowledge will impact many ongoing drug design projects utilizing similar synthetic chemistry for analogue library preparation, including research aimed at the development of novel cardiovascular drugs, bladder overactivity agents, anti-leishmanial compounds among many others.
This project is aimed at the ultimate goal of providing new therapeutic agents for the treatment of cancer. It involves the utilization of a naturally occurring plant metabolite, podophyllotoxin, for the design, preparation and testing of synthetic molecules expected to be toxic to cancer cells.
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