3′-oxo-, amino-, thio- and sulfone-acetic acid modified thymidines: effect of increased acidity on ribonuclease A inhibition

Abstract

A family of 3′-functionalized thymidines carrying XCH₂COOH (X = O, NH, S, SO₂) groups has been designed as inhibitors of RNase A. This is because it is possible to manipulate the overall acidity of this new class of nucleic ‘acids’ by changing X from oxygen to the SO₂ group in the series. It is also expected that the acyclic nature of the XCH₂COOH group would provide enough flexibility to the –COOH group to have maximum interactions with the catalytic subsite P₁ of RNase A. As the –SO₂CH₂COOH substituted derivative showed better potency partially because of the increased acidity of the –COOH group, the inhibitory properties of both 5′-substituted and 3′,5′-disubstituted sulfone acetic acid modified thymidines were investigated. Two –SO₂CH₂COOH groups were incorporated with the expectation of targeting two phosphate binding sites simultaneously. Thus, 3′,5′-dideoxy-3′,5′-bis-S-[(carboxymethyl)sulfonyl]thymidine emerged as the best inhibitor in this series with a K_i value of 25 ± 2 μM.