Journal
CHEMICAL BIOLOGY & DRUG DESIGN
Volume 73, Issue 2, Pages 189-202Publisher
WILEY
DOI: 10.1111/j.1747-0285.2008.00750.x
Keywords
anti-tumor activity; gelatinase inhibitor; metabolism
Funding
- National Institutes of Health [CA122417, CA61986, CA100475]
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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.
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