title: 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; commercial human serum albumin (HSA); a constitutively active mutant of the protein tyrosine phosphatase PRL-1 (PRL-1-C170S-C171S), a model protein; and diluted fresh human plasma. The reaction was followed by high-performance liquid chromatography, 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 was 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.
authors.affiliation: Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas 66047, USA.
authors.forename: Kwame W
authors.initials: KW
authors.lastname: Nti-Addae
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Laurence
authors.forename: Andria L
authors.initials: AL
authors.lastname: Skinner
authors.forename: Valentino J
authors.initials: VJ
authors.lastname: Stella
mesh_terms: D000081:Acetamides / Q000737:chemistry*; D018797:Cell Cycle Proteins / Q000737:chemistry* / Q000235:genetics; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D000069349:Linezolid; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics; D009154:Mutation; D023303:Oxazolidinones / Q000737:chemistry*; D010949:Plasma / Q000737:chemistry; D011355:Prodrugs / Q000737:chemistry*; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry* / Q000235:genetics; D012709:Serum Albumin / Q000737:chemistry*; D013416:Sulfamerazine / Q000737:chemistry*; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D013678:Technology, Pharmaceutical / Q000379:methods
chemical_list: D000081:Acetamides; D018797:Cell Cycle Proteins; D008565:Membrane Proteins; D023303:Oxazolidinones; D011355:Prodrugs; D012709:Serum Albumin; D013438:Sulfhydryl Compounds; C471392:sulfenamide; C490198:PTP4A1 protein, human; D017027:Protein Tyrosine Phosphatases; D000069349:Linezolid; D013416:Sulfamerazine