期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 48, 期 -, 页码 143-152出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2011.12.006
关键词
Organoselenium-saccharide derivative; Ebselen; Cancer; Invasion; Metastasis
资金
- Canadian Institutes of Health Research
- Quebec Breast Cancer Foundation
- Ministry of Science and Technology of the People's Republic of China
- Natural Science Foundation of China [21171154]
The present study reports synthesis and biological activity of novel benzoisoselenazolone compounds derived from ebselen and conjugated to a sugar molecule. Cell proliferation assay using cancer cells combined with in vitro biochemical assays revealed that benzoisoselenazolone 2d, 5a, and 6a exerted anti-proliferative activity, which correlated with selective in vitro inhibition of focal adhesion kinase, AKT-1, and protein kinase C-alpha. Active molecules were able to significantly inhibit cell migration and invasion in vitro compared to cells treated with the vehicle alone or ebselen. Moreover, in vivo anticancer activity focusing on lead compound 2d and using an invasive human breast cancer orthotopic mouse model revealed a potent anti-metastatic activity at well-tolerated doses. In summary, these novel benzoisoselenazolones we report herein target multiple kinases with established roles in cancer progression and possess anti-invasive and anti-metastatic activity in preclinical models supporting a potential for therapeutic application for human disease. Crown Copyright (C) 2011 Published by Elsevier Masson SAS. All rights reserved.
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