The specific aims of the work proposed herein are to design and synthesize inhibitors of purine nucleoside phosphorylase (EC 2.4.2.1) and hypoxanthine phosphoribosyltransferase (EC 2.4.2.8.) and to evaluate them for their ability to inhibit these two enzymes. Effective inhibitors will then be studied for their potential in the treatment of cancer in animal models, particularly in combination with known anticancer agents such as certain purine nucleosides and inhibitors of the de novo pathway to purine nucleotides. The long-term objectives are to learn more about these glycosyl-bond forming enzymes in terms of the enzyme mechanism and substrate binding and to develop new compounds that will be useful in the treatment of cancer, probably in combination chemotherapy, and other diseases such as parasitic infections. This effort will require the collaboration of organic synthetic chemists with biochemists and experimental chemotherapists. If successful, it could result in improved chemotherapy of cancer and of certain parasite infections such as malaria. It could also shed light on the role of PNP deficiency in immunodeficiency, since there are data that strongly suggest that the PNP deficiency impairs the function of a T cell population. In this renewal proposal, the design of most of the proposed inhibitors is based on X-ray crystallographic data on PNP provided by Dr. Charles E. Bugg of the University of Alabama at Birmingham and on the recent discovery of the inhibitory properties of Acyclovir diphosphate.
