Carboxymethylsulfonylated ribopyrimidines: rational design of ribonuclease a inhibitors employing chemical logic

Abstract

Hydrolysis of RNA by ribonuclease A crucially depends on the participation of the 2'-OH group as well as the positioning of the internucleotide bond at two different sites of the enzyme. Therefore, ribopyrimidines were modified with −SO₂CH₂CO₂H, an acidic functional group, which was expected to interact with the phosphate binding site. These ribonucleosides were designed to understand the influence of the 2'-OH group of these inhibitors on ribonuclease A inhibition along with the effect of the −SO₂CH₂CO₂H group. The "down" configuration of the 2'-OH group enhanced the inhibitory properties (K_i = 1.75 μm) and also imparted important Val43 H-bonding with the furanose oxygen atom of the inhibitors. One of the most important aspects of this work is that there was no serendipitous discovery of the inhibitors. The inhibitors reported in this manuscript were obtained by design by employing chemical logic.