title: Metabolism of a highly selective gelatinase inhibitor generates active metabolite.
abstract: (4-Phenoxyphenylsulfonyl)methylthiirane (inhibitor 1) is a highly selective inhibitor of gelatinases (matrix metalloproteinases 2 and 9), which is showing considerable promise in animal models for cancer and stroke. Despite demonstrated potent, selective, and effective inhibition of gelatinases both in vitro and in vivo, the compound is rapidly metabolized, implying that the likely activity in vivo is due to a metabolite rather than the compound itself. To this end, metabolism of inhibitor 1 was investigated in in vitro systems. Four metabolites were identified by LC/MS-MS and the structures of three of them were further validated by comparison with authentic synthetic samples. One metabolite, 4-(4-thiiranylmethanesulfonylphenoxy)phenol (compound 21), was generated by hydroxylation of the terminal phenyl group of 1. This compound was investigated in kinetics of inhibition of several matrix metalloproteinases. This metabolite was a more potent slow-binding inhibitor of gelatinases (matrix metalloproteinase-2 and matrix metalloproteinase-9) than the parent compound 1, but it also served as a slow-binding inhibitor of matrix metalloproteinase-14, the upstream activator of matrix metalloproteinase-2.
authors.affiliation: Department of Chemistry and Biochemistry and the Walther Cancer Research Center, University of Notre Dame, Notre Dame, IN 46556, USA.
authors.forename: Mijoon
authors.initials: M
authors.lastname: Lee
authors.forename: Adriel
authors.initials: A
authors.lastname: Villegas-Estrada
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Celenza
authors.forename: Bill
authors.initials: B
authors.lastname: Boggess
authors.forename: Marta
authors.initials: M
authors.lastname: Toth
authors.forename: Gloria
authors.initials: G
authors.lastname: Kreitinger
authors.forename: Christopher
authors.initials: C
authors.lastname: Forbes
authors.forename: Rafael
authors.initials: R
authors.lastname: Fridman
authors.forename: Shahriar
authors.initials: S
authors.lastname: Mobashery
authors.forename: Mayland
authors.initials: M
authors.lastname: Chang
mesh_terms: D015195:Drug Design; D018093:Gelatinases / Q000037:antagonists & inhibitors*; D006801:Humans; D007700:Kinetics; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013379:Substrate Specificity
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D018093:Gelatinases