title: Active site ring-opening of a thiirane moiety and picomolar inhibition of gelatinases.
abstract: (+/-)-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.
authors.affiliation: Department of Chemistry and Biochemistry and Walther Cancer Research Center, University of Notre Dame, Notre Dame, IN 46556, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Forbes
authors.forename: Qicun
authors.initials: Q
authors.lastname: Shi
authors.forename: Jed F
authors.initials: JF
authors.lastname: Fisher
authors.forename: Mijoon
authors.initials: M
authors.lastname: Lee
authors.forename: Dusan
authors.initials: D
authors.lastname: Hesek
authors.forename: Leticia I
authors.initials: LI
authors.lastname: Llarrull
authors.forename: Marta
authors.initials: M
authors.lastname: Toth
authors.forename: Michael
authors.initials: M
authors.lastname: Gossing
authors.forename: Rafael
authors.initials: R
authors.lastname: Fridman
authors.forename: Shahriar
authors.initials: S
authors.lastname: Mobashery
mesh_terms: D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry* / Q000494:pharmacology; D007700:Kinetics; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D056004:Molecular Dynamics Simulation; D013237:Stereoisomerism; D013450:Sulfones / Q000737:chemistry* / Q000494:pharmacology; D015032:Zinc / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D006573:Heterocyclic Compounds, 1-Ring; D061965:Matrix Metalloproteinase Inhibitors; C429533:SB 3CT compound; D013450:Sulfones; D020778:Matrix Metalloproteinase 2; D015032:Zinc