Linear free energy-related and quantitative structure-activity relationships of inhibitors of thymidylate synthetase.

Thirteen previously described 5-(p-substituted-phenyl)-2'-deoxyuridines were synthesized, and the NMR and IR spectra of their 2,4-dioxopyrimidine (2,4-DP) rings were correlated against linear free energy-related and extrathermodynamic parameters. We conclude that the 5-phenyl ring is probably oriented over the plane of the 2,4-DP ring (sandwich structure, Figure 6). The main component of the spectroscopic data is largely determined by the stereoelectronic nature of the para-groups in the 5-phenyl ring, while a second component is largely determined by apolar forces. The inhibitory activity of the compounds against thymidylate synthetase is enhanced by the presence of apolar groups with a positive inductive effect, provided these groups do not extend the plane of the 2,4-DP ring.