Active Site Ring-Opening of a Thiirane Moiety and Picomolar Inhibition of Gelatinases

作者：Forbes Christopher; Shi Qicun; Fisher Jed F; Lee Mijoon; Hesek Dusan; Llarrull Leticia I; Toth Marta; Gossing Michael; Fridman Rafael; Mobashery Shahriar^*

来源：Chemical Biology & Drug Design, 2009, 74(6): 527-534.

DOI：10.1111/j.1747-0285.2009.00881.x

• latent thiolate
• thiirane
• tight-binding inhibition
• zinc protease

(+/-)-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.

• 出版日期2009-12