The proposed study is based upon the successful synthesis of the first specific, potent multisubstrate analog inhibitor of the enzyme thymidylate synthetase. The prototype inhibitor consists of a 5,6,7,8-tetrahydro-8-deazafolate linked at N5 through a methylene bridge to C5 of 2'-deoxyuridylate. The inhibitor will be modified chemically in specific ways designed to (a) explore the active site of thymidylate synthetase through modification of the p-aminobenzoyl glutamate side chain (b) reduce the charge and increase the lipohilicity of these highly polar molecules such that entry to intact cells and subsequent conversion to active inhibitor may occur and (c) develop a """"""""second generation"""""""" of flexible analogs expected to have still greater potency and specificity for the thymidylate synthetase. This approach should provide not only biochemical probes for elucidating the effects of specific inhibition of this key enzyme, but may also provide useful antitumor and, perhaps, antiviral agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA037601-03
Application #
3175382
Study Section
Biochemistry Study Section (BIO)
Project Start
1984-03-01
Project End
1987-08-31
Budget Start
1986-03-01
Budget End
1987-08-31
Support Year
3
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Utah
Department
Type
Schools of Pharmacy
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112