title: DFT studies of the ring-opening mechanism of SB-3CT, a potent inhibitor of matrix metalloproteinase 2.
abstract: SB-3CT is a 2-[(arylsulfonyl)methyl]thiirane that achieves potent inhibition, by a thiirane-opening mechanism, of the MMP2 and MMP9 zinc metalloproteases. The deprotonation mechanism for thiirane opening of SB-3CT and for the opening of its oxirane analogue, both relevant to the inhibition of MMP2, was investigated computationally using the acetate anion as the Brønsted base and in methanol and acetonitrile as solvents. The activation barriers for the reaction show a significant stereoelectronic effect. The lowest energy paths have the breaking C-H bond gauche to both sulfone oxygens and with this C-H bond anti to the breaking C-S bond of the thiirane. The calculated primary isotope effect agrees with experimental data.
authors.affiliation: Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Tao
authors.forename: Jed F
authors.initials: JF
authors.lastname: Fisher
authors.forename: Shahriar
authors.initials: S
authors.lastname: Mobashery
authors.forename: H Bernhard
authors.initials: HB
authors.lastname: Schlegel
mesh_terms: D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry* / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry*; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry; D061965:Matrix Metalloproteinase Inhibitors; D015394:Molecular Structure; 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; D020780:Matrix Metalloproteinase 9; D015032:Zinc