| In this project, a variety of 5-substituted-6-[(2-aminoimidazol-l'-yl)methyl]uracils were rationally designed, synthesized and tested as potential thymidine phosphorylase inhibitors.; These results are consistent with the hypothesis that the electron-withdrawing effect of the substituent at the 5-position, as reflected by the pKa-values of the analogs, enhances the affinity of the inhibitors for the enzyme.; Molecular modeling studies of these compounds in the active site of human thymidine phosphorylase was used to rationalize their inhibitory activities. While compounds 2, 6 and 8 bound tightly to the active site of the enzyme, the steric bulk of the trifluoromethyl group prevented compound 4 from being fully accommodated in the spatially restricted and highly organized closed form of the enzyme active site, in spite of its hydrophobicity and favorable electronic properties. (Abstract shortened by UMI.)... |
