Reversion of Sulfenamide Prodrugs in the Presence of Free Thiol Containing Proteins

Abstract

The purpose of this work was to study the reaction kinetics between two model sulfenamide prodrugs of linezolid, N-(phenylthio)linezolid and N-((2-ethoxycarbonyl)ethylthio)linezolid, with free thiol containing proteins; human serum albumin (HSA); a constitutively active mutant of theprotein tyrosine phosphatase PRL-1, PRL-1-C170-171S, a model protein; and diluted fresh human plasma. The reaction was followed by HPLC, both for the loss of prodrug and appearance of linezolid, and at different pH values with molar excess of the proteins relative to the prodrugs. Pseudo first-order kinetics were observed. Consistent with earlier findings for the reaction between similar sulfenamides and small molecule thiols, the reaction kinetics appeared to be consistent with thiolate attack at the sulfenamide bond to release the parent drug. The proteins reacted significantly slower on a molar basis than their small molecule counterparts. It appears that proteins such as HSA may play a role in the in vivo conversion of sulfenamide prodrugs to their parent drug.