IRREVERSIBLE ENZYME INHIBITORS .121. THYMIDINE PHOSPHORYLASE .9. ON NATURE AND DIMENSIONS OF HYDROPHOBIC BONDING REGION

The dimensions of the hydrophobic bonding region of E. coli B thymidine phosphorylase have been studied with 25 derivatives of 6-anilinouracil (4) and four derivatives of 6-benzyIammouraciI (5), where substituents have been placed on the benzene ring of these two compounds. One side of the benzyl group of 5 is hydrophobicallv bonded and the other side is not. Similarly, the opposite side of the phenyl group of 4 is hydrophobically bonded and the other is not; it is in these nonhvdrophobic regions where the benzene rings should be substituted with appropriate leaving groups in order to convert 4 and 5 to active-site-directed irreversible inhibitors. The hydrophobic bonding region on the enzyme is fairly planar since bicyclic and tricyclic systems such as 3- and 4-aminobiphenyl, ±- and (²-naphthylamine, and 2-anthranylamino (31) attached to the 6 position of uracil are effectively complexed to the enzyme; in fact, 31 and 6-(2,3-dichloroanilino)uracil (23) are inhibitors that complex to thymidine phosphorylase 1100-fold more effectively than the substrate, 5-fluoro-2'-deoxyuridine (FUDR). © 1968, American Chemical Society. All rights reserved.