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A Potent Gelatinase Inhibitor with Anti‐Tumor‐Invasive Activity and its Metabolic Disposition
Author(s) -
Lee Mijoon,
Celenza Giuseppe,
Boggess Bill,
Blase Jennifer,
Shi Qicun,
Toth Marta,
Bernardo M. Margarida,
Wolter William R.,
Suckow Mark A.,
Hesek Dusan,
Noll Bruce C.,
Fridman Rafael,
Mobashery Shahriar,
Chang Mayland
Publication year - 2009
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2008.00750.x
Subject(s) - thiirane , ht1080 , matrix metalloproteinase , chemistry , gelatinases , biochemistry , fibrosarcoma , pharmacology , cancer research , enzyme , gelatinase , biology , medicine , ring (chemistry) , pathology , in vitro , organic chemistry
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.