This research is a study of the design and synthesis of agents useful primarily in the treatment of cancer and viral infections. The approach used is to study the chemical and physical properties of the metabolic sequence that may be one of the controlling or limiting processes in the synthesis of deoxyribonucleic acid and ultimately cell division. The sequence is the reductive methylation of deoxyuridine-5'-phosphate catalyzed by the enzyme thymidylate synthetase. The research objective of this problem is a study of the synthesis and in vitro testing of potential thymidylate synthetase inhibitors.
The specific aims of this proposal are: a) a mechanism study of the second step in the enzyme catalyzed reaction, b) the synthesis of isoenzyme specific inhibitors c) the design and synthesis of mechanism based affinity labels, kcat inhibitors, and photoaffinity labels, d) in vitro enzyme inhibition studies including active site labelling studies e) anticancer and antiviral evaluation f) in vivo thymidylate synthetase studies.
