title: A potent gelatinase inhibitor with anti-tumor-invasive activity and its metabolic disposition.
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 alpha-methylene, which generates sulfinic acid, thiirane ring-opening, followed by methylation and oxidation, and cysteine conjugation of both the thiirane and phenyl rings.
authors.affiliation: Department of Chemistry and Biochemistry and Walther Cancer Research Center, University of Notre Dame, Notre Dame, IN 46556, USA.
authors.forename: Mijoon
authors.initials: M
authors.lastname: Lee
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Celenza
authors.forename: Bill
authors.initials: B
authors.lastname: Boggess
authors.forename: Jennifer
authors.initials: J
authors.lastname: Blase
authors.forename: Qicun
authors.initials: Q
authors.lastname: Shi
authors.forename: Marta
authors.initials: M
authors.lastname: Toth
authors.forename: M Margarida
authors.initials: MM
authors.lastname: Bernardo
authors.forename: William R
authors.initials: WR
authors.lastname: Wolter
authors.forename: Mark A
authors.initials: MA
authors.lastname: Suckow
authors.forename: Dusan
authors.initials: D
authors.lastname: Hesek
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Noll
authors.forename: Rafael
authors.initials: R
authors.lastname: Fridman
authors.forename: Shahriar
authors.initials: S
authors.lastname: Mobashery
authors.forename: Mayland
authors.initials: M
authors.lastname: Chang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D045744:Cell Line, Tumor; D019295:Computational Biology; D005260:Female; D018093:Gelatinases / Q000037:antagonists & inhibitors*; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D008698:Mesylates / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness / Q000517:prevention & control
chemical_list: C539569:4-(4-(thiiranylmethylsulfonyl)phenoxy)-phenyl methanesulfonate; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D061965:Matrix Metalloproteinase Inhibitors; D008698:Mesylates; D018093:Gelatinases