Synthesis and biological activity of novel organoselenium derivatives targeting multiple kinases and capable of inhibiting cancer progression to metastases

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• 作者：Krikor Bijian^a ; ^b ; ¹ ; Zhongwei Zhang^c ; ¹ ; Bin Xu^a ; ^b ; Su Jie^a ; ^b ; Bo Chen^c ; Shengbiao Wan^c ; JianHui Wu^a ; ^b ; Tao Jiang^c ; ^{jiangtao@ouc.edu.cn} ; Moulay A. Alaoui-Jamali^a ; ^b ; ^{moulay.alaoui-jamali@mcgill.ca}
• 关键词：Organoselenium-saccharide derivative ; Ebselen ; Cancer ; Invasion ; Metastasis
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：February, 2012
• 年：2012
• 卷：48
• 期：Complete
• 页码：143-152
• 全文大小：877 K

文摘

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 rong class=""boldFont"">2drong>, rong class=""boldFont"">5arong>, and rong class=""boldFont"">6arong> exerted anti-proliferative activity, which correlated with selective in?vitro inhibition of focal adhesion kinase, AKT-1, and protein kinase C-¦Á. 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 rong class=""boldFont"">2drong> 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.