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Active Site Ring‐Opening of a Thiirane Moiety and Picomolar Inhibition of Gelatinases
Author(s) -
Forbes Christopher,
Shi Qicun,
Fisher Jed F.,
Lee Mijoon,
Hesek Dusan,
Llarrull Leticia I.,
Toth Marta,
Gossing Michael,
Fridman Rafael,
Mobashery Shahriar
Publication year - 2009
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2009.00881.x
Subject(s) - thiirane , gelatinases , chemistry , matrix metalloproteinase , matrix metalloproteinase inhibitor , gelatinase a , active site , gelatinase , stereochemistry , biochemistry , enzyme , ring (chemistry) , organic chemistry
(±)‐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 p m 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.