FRANK BLOCK

Date of Award

Spring 1980

Project Type

Dissertation

Program or Major

Chemistry

Degree Name

Doctor of Philosophy

Abstract

5-fluorouracil is a chemotherapeutic agent which is used in the treatment of disseminated colon and breast cancers. As an antimetabolite it has been found to inhibit the mechanism in which the normal substrate reacts with the enzyme and a cofactor in nucleic acid synthesis. A number of mechanisms have been summarized describing the conversion of deoxyuridylate (dUMP) to deoxythymidylate (dTMP), elucidating the role of the involved enzyme, thymidylate synthetase, and the co-factor, N('5), N('10)-methylenetetrahydrofolate. The effect of replacing the hydrogen bonded to the 5-position of the pyrimidine ring by a fluorine atom is also mechanistically described. A molecular orbital study employing the CNDO/2 approximation was performed on 5-fluorouracil, uracil, and thymine and the results support the mechanisms and chemical effects drawn from the literature which center around the bond polarization of the 5,6 double bond of uracil. The electronic effects of fluorine substitution (in 5-fluorouracil) are also consistent with formation of a more stable enzyme-substrate complex and with favorable kinetic competition of 5-fluorouracil with uracil for the enzymatic nucleophilic site.

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