Interaction of thymidylate synthase with 5-fluoro-substituted DUMP analogues in view of the pyrimidine ring structure

To explain the mechanism of the influence of fluorine substituent on the FdUMP activity in thymidylate synthase reaction, the aromaticity based on X-ray determined structures, factor analysis applied to structural data from CSD and ab initio RHF calculations were employed. It was found that fluorine substitution dearomatizes the pyrimidine ring, stabilizing the local double C(5)=C(6) bond and making them more susceptible to nucleophilic addition from the thymidylate synthase side. The effect of local strain occurs in the ipso region in relation to the substituent. The effect is rather asymmetrical: the C(5)=C(6) bond is more strongly affected by the substituent than the C(4)-C(5) bond. This suggests a possibility of a further affinity increase of FdUMP system regarding the enzyme.