Metabolism of (4-phenoxyphenylsulfonyl) methylthiirane, a selective gelatinase inhibitor.
(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
Celenza
Giuseppe
G
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
Villegas-Estrada
Adriel
A
Lee
Mijoon
M
Boggess
Bill
B
Forbes
Christopher
C
Wolter
William R
WR
Suckow
Mark A
MA
Mobashery
Shahriar
S
Chang
Mayland
M
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D018093:Gelatinases / Q000037:antagonists & inhibitors*; D005978:Glutathione / Q000378:metabolism; D006573:Heterocyclic Compounds, 1-Ring / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D021241:Spectrometry, Mass, Electrospray Ionization; D013450:Sulfones / Q000378:metabolism*; D053719:Tandem Mass Spectrometry
D004791:Enzyme Inhibitors; D006573:Heterocyclic Compounds, 1-Ring; C429533:SB 3CT compound; D013450:Sulfones; D018093:Gelatinases; D005978:Glutathione