IRREVERSIBLE ENZYME INHIBITORS .162. HYDROPHOBIC BONDING TO CYTOSINE NUCLEOSIDE DEAMINASE WITH 1-SUBSTITUTED 5-ARYLCYTOSINES

1-Phenoxypmpyl-5-phenylcytosine (2) was previously reported3b to be an inhibitor of cytosine nucleoside deaminase that was complexed one-fourth as well as the substrate, 2′-deoxycytidine. In order to enhance the activity of 2, 41 variants were synthesized for evaluation: (a) the 1-phenoxypropyl moiety was as good or better than five other 1 substituents studied: (b) when the 5-phenyl group was substituted with ten different groups, optimum binding occurred with the 3,4-Cl2 substituents: (c) 15 different substituents on the phenoxy moiety gave little change in binding, but showed good bulk tolerance for the large benzamido substituent; (d) five combinations of the substituents on the 2,4 positions of the pyrimidine moiety gave optimum binding with the 2-oxo-4-thione combination. Among the best inhibitors derived from 5-(3,4-dichlorophenylCytosine were the 1-(p-chlorophenoxypropyl) (26) and 1-(m-benzamidophenoxypropyl) (37) derivatives whichwere complexed threefold better to the enzyme than the substrate. © 1969, American Chemical Society. All rights reserved.