Synthesis, Kinetic Characterization and Metabolism of Diastereomeric 2-(1-(4-Phenoxyphenylsulfonyl)ethyl)thiiranes as Potent Gelatinase and MT1-MMP Inhibitors

Authors

  • Major Gooyit,

    1. Department of Chemistry and Biochemistry and Walther Cancer Research Center, University of Notre Dame, Notre Dame, IN 46556, USA
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  • Mijoon Lee,

    1. Department of Chemistry and Biochemistry and Walther Cancer Research Center, University of Notre Dame, Notre Dame, IN 46556, USA
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  • Dusan Hesek,

    1. Department of Chemistry and Biochemistry and Walther Cancer Research Center, University of Notre Dame, Notre Dame, IN 46556, USA
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  • Bill Boggess,

    1. Department of Chemistry and Biochemistry and Walther Cancer Research Center, University of Notre Dame, Notre Dame, IN 46556, USA
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  • Allen G. Oliver,

    1. Department of Chemistry and Biochemistry and Walther Cancer Research Center, University of Notre Dame, Notre Dame, IN 46556, USA
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  • Rafael Fridman,

    1. Department of Pathology, Wayne State University School of Medicine, and Proteases and Cancer Program, Karmanos Cancer Institute, Detroit, MI 48201, USA
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  • Shahriar Mobashery,

    Corresponding author
    1. Department of Chemistry and Biochemistry and Walther Cancer Research Center, University of Notre Dame, Notre Dame, IN 46556, USA
      *Corresponding authors: Shahriar Mobashery, mobashery@nd.edu, Mayland Chang, mchang@nd.edu
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  • Mayland Chang

    Corresponding author
    1. Department of Chemistry and Biochemistry and Walther Cancer Research Center, University of Notre Dame, Notre Dame, IN 46556, USA
      *Corresponding authors: Shahriar Mobashery, mobashery@nd.edu, Mayland Chang, mchang@nd.edu
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*Corresponding authors: Shahriar Mobashery, mobashery@nd.edu, Mayland Chang, mchang@nd.edu

Abstract

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 α-position to the sulfonyl group. α-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 α-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.

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