Metabolism of (4-phenoxyphenylsulfonyl)methylthiirane, a selective gelatinase inhibitor

Giuseppe Celenza, Adriel Villegas-Estrada, Mijoon Lee, Bill Boggess, Christopher Forbes, William R. Wolter, Mark A. Suckow, Shahriar Mobashery, Mayland Chang

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

(4-Phenoxyphenylsulfonyl)methylthiirane (compound 1) is a highly selective and potent inhibitor of gelatinases that shows considerable promise in animal models for cancer and stroke. The metabolism of compound 1 was investigated in mice, following intraperitoneal administration at 100 mg/kg. Eight metabolites were identified in plasma and urine. The primary routes of metabolism of 1 were hydroxylation at the para-position of the terminal phenyl ring, hydroxylation at the α-methylene to the sulfonyl, which lead to the generation of a sulfinic acid, and cysteine conjugation of the thiirane ring. The cysteine adducts arose through addition of glutathione to the thiirane ring. The molecule is extensively metabolized and excreted in mice, yet it exhibits activity in vivo.

Original languageEnglish (US)
Pages (from-to)187-196
Number of pages10
JournalChemical Biology and Drug Design
Volume71
Issue number3
DOIs
StatePublished - Mar 2008

Keywords

  • Gelatinase inhibitor
  • Glutathione adduct
  • Metabolism

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