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: 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
• Journal: Chemical biology & drug design (Chem Biol Drug Des) Vol. 73 Issue 2 Pg. 189-202 (Feb 2009) ISSN: 1747-0285 [Electronic] England
• PMID: 19207421 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 4-(4-(thiiranylmethylsulfonyl)phenoxy)-phenyl methanesulfonate
• Antineoplastic Agents
• Biphenyl Compounds
• Matrix Metalloproteinase Inhibitors
• Mesylates
• Gelatinases

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, toxicity)
• Biphenyl Compounds (chemical synthesis, chemistry, toxicity)
• Cell Line, Tumor
• Computational Biology
• Female
• Gelatinases (antagonists & inhibitors)
• Humans
• Matrix Metalloproteinase Inhibitors
• Mesylates (chemical synthesis, chemistry, toxicity)
• Mice
• Mice, Inbred BALB C
• Neoplasm Invasiveness (prevention & control)