title: Thiolytic chemistry of alternative precursors to the major metabolite of the cancer chemopreventive oltipraz.
abstract: The compounds 7-methyl-6,8-bis(methyldisulfanyl)pyrrolo[1,2-a]pyrazine (5; "bis disulfide") and methanethiosulfonic acid S-((6-(methanesulfonylsulfanyl)-7-methyl)pyrrolo[1,2-a]pyrazin-8-yl) ester (6; "bis methanesulfonic acid thioester") have been synthesized to serve as alternative precursors to the major metabolite, 4, of the cancer chemopreventive oltipraz, 1, to test whether they possess similar biological activities. In the present work the mechanisms by which these compounds react with glutathione have been investigated in order to validate the assumption that they would be chemically competent in the presence of the biological thiols to give the oltipraz metabolite. A kinetic and product study was carried out in mainly aqueous media, </=15% ethanol by volume, at 37 degrees C. The kinetic analysis and identification of intermediates by electrospray HPLC/MS indicate that compound 5 decomposes in two sequential reactions via thiol-disulfide interchange involving removal of the two thiomethyl groups. In contrast, 6 decomposes in three sequential steps, the first entailing formation of the diglutathionyl adduct, followed by two subsequent thiol disulfide interchange reactions involving loss of the glutathionyl moieties. Both 5 and 6, as well as oltipraz itself, give nearly quantitative yields of the metabolite 4 in reactions with glutathione. Analysis of the decay of 6 by EPR spin trapping methods indicates that less than 0.2% of the reaction flux proceeds through radicals more stable than the hydroxyl radical.
authors.affiliation: Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, Maryland 21250, USA.
authors.forename: Mettachit
authors.initials: M
authors.lastname: Navamal
authors.forename: Colleen
authors.initials: C
authors.lastname: McGrath
authors.forename: Jennifer
authors.initials: J
authors.lastname: Stewart
authors.forename: Patrick
authors.initials: P
authors.lastname: Blans
authors.forename: Frederick
authors.initials: F
authors.lastname: Villamena
authors.forename: Jay
authors.initials: J
authors.lastname: Zweier
authors.forename: James C
authors.initials: JC
authors.lastname: Fishbein
mesh_terms: D000465:Algorithms; D016588:Anticarcinogenic Agents / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals; D005978:Glutathione / Q000032:analysis / Q000737:chemistry*; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry*; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D013871:Thiones; D013876:Thiophenes
chemical_list: D016588:Anticarcinogenic Agents; D005609:Free Radicals; D011719:Pyrazines; D013438:Sulfhydryl Compounds; D013871:Thiones; D013876:Thiophenes; C026209:oltipraz; D005978:Glutathione