Design of species- or isozyme-specific enzyme inhibitors. I. Effect of thymidine substituents on affinity for the thymidine site of hamster cytoplasmic thymidine kinase

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Abstract
5-(Ethylamino)- and 5-acetamido-2''-deoxyuridine 5''-triphosphates were synthesized; the extent and concentration dependence of their inhibitory action on the title enzyme resembled that of the feedback inhibitor TTP. This and other findings provide a tentative indication that bulk tolerance near C-5 of the thymine ring may be more extensive at the TTP site than at the thymidine site. Enzyme-inhibitor dissociation constants (Ki values) were determined for thymidine derivatives monosubstituted at various positions. Competitive inhibition with respect to thymidine (indicative of substituent tolerance in the enzyme-thymidine complex) was produced by 3-amylthymidine (Ki = 65 .mu.M), trans-5-bromo-6-ethoxy-5,6-dihydrothymidine diastereoisomers (Ki = 180 and 310 .mu.M), 5''-C-(acetamidomethyl)- and 5-C-(propionamidomethyl)thymidine epimers (Ki range 65-1100 .mu.M), 3''-acetamido- and 3''-(ethylthio)-3''-deoxythymidines (Ki range 180-1200 .mu.M). Evidence indicates that bulk tolerance at some, if not most, of the above atoms of thymidine is found in the enzyme-thymidine complexes of human and other mammalian thymidine kinases; attachment of suitable substituents to such atoms could, in principle, lead to thymidine site directed isozyme-specific inhibitors of human cytoplasmic thymidine kinase, which is a candidate target in the design of antineoplastic drugs.

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