IRREVERSIBLE ENZYME INHIBITORS .130. CYTOSINE NUCLEOSIDE DEAMINASE .I. HYDROPHOBIC BONDING WITH MONOSUBSTITUTED URACILS

Thirty-eight derivatives of uracil and five derivatives of thymidine have been investigated as inhibitors of the cytosine nucleoside deaminase from E. coli B. Hydrophobic bonding to the enzyme could be detected with 1- substituted uracils, 6-substituted uracils, and 5′-substituted thymidines. Thymidine itself is a weak inhibitor of this enzyme and was employed as the base-line standard compound. The best inhibitors of the 1-substituted uracil class were 1-phenylbutyl- (15), l-phenylamyl- (16), and 1-pheuoxypropyluracil (18) which were eomplexed to the enzyme about as effectively as thymidine. The best inhibitors of the 6-substituted uracil class were 0-benzyl- (25) and 6-phenylpropyluracil (26) which were also eomplexed as well as thymidine. In the thymidine series, the best inhibitors were the 5′-O-carbopheuoxy (37) and 5-O-(N-phenylpropylcarbamoyl) (38) derivatives which were 3-4-fold more effective than thymidine; in contrast, 5′-O-carbamoylthymidine (35) was less effective than thymidine. The possible biological role of this hydrophobic bonding region adjacent to the active site of cytosine nucleoside deaminase is discussed. © 1968, American Chemical Society. All rights reserved.