A potent gelatinase inhibitor with anti-tumor-invasive activity and its metabolic disposition

Mijoon Lee, Giuseppe Celenza, Bill Boggess, Jennifer Blase, Qicun Shi, Marta Toth, M. Margarida Bernardo, William R. Wolter, Mark A. Suckow, Dusan Hesek, Bruce C. Noll, Rafael Fridman, Shahriar Mobashery, Mayland Chang

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Metastatic tumors lead to more than 90% fatality. Despite the importance of invasiveness of tumors to poor disease outcome, no anti-invasive compounds have been commercialized. We describe herein the synthesis and evaluation of 4-(4-(thiiranylmethylsulfonyl)phenoxy)-phenyl methanesulfonate (compound 2) as a potent and selective inhibitor of gelatinases (matrix metalloproteinases-2 and -9), two enzymes implicated in invasiveness of tumors. It was demonstrated that compound 2 significantly attenuated the invasiveness of human fibrosarcoma cells (HT1080). The metabolism of compound 2 involved hydroxylation at the α-methylene, which generates sulfinic acid, thiirane ring-opening, followed by methylation and oxidation, and cysteine conjugation of both the thiirane and phenyl rings.

Original languageEnglish (US)
Pages (from-to)189-202
Number of pages14
JournalChemical Biology and Drug Design
Volume73
Issue number2
DOIs
StatePublished - Feb 2009

Keywords

  • Anti-tumor activity
  • Gelatinase inhibitor
  • Metabolism

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