Synthesis, kinetic characterization and metabolism of diastereomeric 2-(1-(4-phenoxyphenylsulfonyl)ethyl)thiiranes as potent gelatinase and MT1-MMP inhibitors.
Gelatinases (MMP-2 and MMP-9) have been implicated in a number of pathological conditions, including cancer and cardiovascular disease. Hence, small molecule inhibitors of these enzymes are highly sought for use as potential therapeutic agents. 2-(4-Phenoxyphenylsulfonylmethyl)thiirane (SB-3CT) has previously been demonstrated to be a potent and selective inhibitor of gelatinases, however, it is rapidly metabolized because of oxidation at the para position of the phenoxy ring and at the alpha-position to the sulfonyl group. alpha-Methyl variants of SB-3CT were conceived to improve metabolic stability and as mechanistic probes. We describe herein the synthesis and evaluation of these structural variants as potent inhibitors of gelatinases. Two (compounds 5b and 5d) among the four synthetic stereoisomers were found to exhibit slow-binding inhibition of gelatinases and MMP-14 (MT1-MMP), which is a hallmark of the mechanism of this class of inhibitors. The ability of these compounds to inhibit MMP-2, MMP-9, and MMP-14 could target cancer tissues more effectively. Metabolism of the newly synthesized inhibitors showed that both oxidation at the alpha-position to the sulfonyl group and oxidation at the para position of the terminal phenyl ring were prevented. Instead oxidation on the thiirane sulfur is the only biotransformation pathway observed for these gelatinase inhibitors.
Gooyit
Major
M
Department of Chemistry and Biochemistry and Walther Cancer Research Center, University of Notre Dame, Notre Dame, IN 46556, USA.
Lee
Mijoon
M
Hesek
Dusan
D
Boggess
Bill
B
Oliver
Allen G
AG
Fridman
Rafael
R
Mobashery
Shahriar
S
Chang
Mayland
M
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003461:Crystallography; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D018093:Gelatinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D013058:Mass Spectrometry; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008862:Microsomes, Liver / Q000378:metabolism; D008968:Molecular Conformation; D010084:Oxidation-Reduction; D051381:Rats; D013237:Stereoisomerism; D013450:Sulfones / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology
D004791:Enzyme Inhibitors; D006573:Heterocyclic Compounds, 1-Ring; D061965:Matrix Metalloproteinase Inhibitors; C429533:SB 3CT compound; D013450:Sulfones; D018093:Gelatinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D053511:Matrix Metalloproteinase 14