Thiolytic chemistry of alternative precursors to the major metabolite of the cancer chemopreventive oltipraz

Mettachit Navamal, Colleen McGrath, Jennifer Stewart, Patrick Blans, Frederick Villamena, Jay Zweier, James C. Fishbein

Research output: Contribution to journalArticlepeer-review

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 °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.

Original languageEnglish (US)
Pages (from-to)9406-9413
Number of pages8
JournalJournal of Organic Chemistry
Volume67
Issue number26
DOIs
StatePublished - Dec 27 2002

ASJC Scopus subject areas

  • Organic Chemistry

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