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. 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

Christopher Forbes  1 , Qicun Shi, Jed F Fisher, Mijoon Lee, Dusan Hesek, Leticia I Llarrull, Marta Toth, Michael Gossing, Rafael Fridman, Shahriar Mobashery
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Active site ring-opening of a thiirane moiety and picomolar inhibition of gelatinases

Christopher Forbes et al. Chem Biol Drug Des. 2009 Dec.

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.

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Figures

Figure 1
Figure 1
Fractional velocity plots showing the tight-binding inhibition of MMP-2 by 7. Morrison’s quadratic equation was used to fit the data.
Figure 2
Figure 2
Two ns dynamics simulations of the complexes of MMP-2 with R-1 (panel A) and S-1 (panel B). The thiirane sulfur of each compound coordinates to the active site zinc ion. The distances between the Glu404 carboxylate oxygens, and the diastereotopic methylene hydrogens of the α-carbon to the sulfone, are shown as a function of the duration of the simulations.
Scheme 1
Scheme 1
Two limiting mechanisms of gelatinase inhibition by 1: (A) Enzyme inhibition occurs by thiirane alkylation of the active site Glu404. (B) Enzyme inhibition occurs by Glu404-dependent deprotonation at the methylene adjacent to the sulfone, initiating ring opening of the thiirane and formation of a stable zinc-thiolate complex.
Scheme 2
Scheme 2
Base-mediated solvolysis of 1. Full experimental details are provided in the Supporting Information.
See this image and copyright information in PMC

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