A potent gelatinase inhibitor with anti-tumor-invasive activity and its metabolic disposition.
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.
Lee
Mijoon
M
Department of Chemistry and Biochemistry and Walther Cancer Research Center, University of Notre Dame, Notre Dame, IN 46556, USA.
Celenza
Giuseppe
G
Boggess
Bill
B
Blase
Jennifer
J
Shi
Qicun
Q
Toth
Marta
M
Bernardo
M Margarida
MM
Wolter
William R
WR
Suckow
Mark A
MA
Hesek
Dusan
D
Noll
Bruce C
BC
Fridman
Rafael
R
Mobashery
Shahriar
S
Chang
Mayland
M
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
C539569:4-(4-(thiiranylmethylsulfonyl)phenoxy)-phenyl methanesulfonate; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D061965:Matrix Metalloproteinase Inhibitors; D008698:Mesylates; D018093:Gelatinases