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

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 alpha-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

• Authors: Giuseppe Celenza, Adriel Villegas-Estrada, Mijoon Lee, Bill Boggess, Christopher Forbes, William R Wolter, Mark A Suckow, Shahriar Mobashery, Mayland Chang
• Journal: Chemical biology & drug design (Chem Biol Drug Des) Vol. 71 Issue 3 Pg. 187-96 (Mar 2008) ISSN: 1747-0285 [Electronic] England
• PMID: 18221479 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Enzyme Inhibitors
• Heterocyclic Compounds, 1-Ring
• SB 3CT compound
• Sulfones
• Gelatinases
• Glutathione

Topics

• Animals
• Enzyme Inhibitors (pharmacology)
• Female
• Gelatinases (antagonists & inhibitors)
• Glutathione (metabolism)
• Heterocyclic Compounds, 1-Ring (metabolism)
• Mice
• Mice, Inbred BALB C
• Microsomes, Liver (enzymology, metabolism)
• Rats
• Spectrometry, Mass, Electrospray Ionization
• Sulfones (metabolism)
• Tandem Mass Spectrometry