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Chem Biol Drug Des. 2009 Dec;74(6):527-34. doi: 10.1111/j.1747-0285.2009.00881.x. Epub 2009 Oct 6.

Active site ring-opening of a thiirane moiety and picomolar inhibition of gelatinases.

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Department of Chemistry and Biochemistry and Walther Cancer Research Center, University of Notre Dame, Notre Dame, IN 46556, USA.


(+/-)-2-[(4-Phenoxyphenylsulfonyl)methyl]thiirane 1 is a potent and selective mechanism-based inhibitor of the gelatinase sub-class of the zinc-dependent matrix metalloproteinase family. Inhibitor 1 has excellent activity in in vivo models of gelatinase-dependent disease. We demonstrate that the mechanism of inhibition is a rate-limiting gelatinase-catalyzed thiolate generation via deprotonation adjacent to the thiirane, with concomitant thiirane opening. A corollary to this mechanism is the prediction that thiol-containing structures, related to thiirane-opened 1, will possess potent matrix metalloproteinase inhibitory activity. This prediction was validated by the synthesis of the product of this enzyme-catalyzed reaction on 1, which exhibited a remarkable K(i) of 530 pm against matrix metalloproteinase-2. Thiirane 1 acts as a caged thiol, unmasked selectively in the active sites of gelatinases. This mechanism is unprecedented in the substantial literature on inhibition of zinc-dependent hydrolases.

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