Synthesis and biological activity of novel organoselenium derivatives targeting multiple kinases and capable of inhibiting cancer progression to metastases.
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-α. 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.
The Segal Cancer Center and Lady Davis Institute of the Sir Mortimer Jewish General Hospital, Montreal, Quebec, Canada.
Krikor
K
Bijian
Zhongwei
Z
Zhang
Bin
B
Xu
Su
S
Jie
Bo
B
Chen
Shengbiao
S
Wan
JianHui
J
Wu
Tao
T
Jiang
Moulay A
MA
Alaoui-Jamali
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006027:Glycosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D016513:Mice, SCID; D008958:Models, Molecular; D009362:Neoplasm Metastasis; D016566:Organoselenium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism
D000970:Antineoplastic Agents; D006027:Glycosides; D016566:Organoselenium Compounds; D047428:Protein Kinase Inhibitors; D051417:Focal Adhesion Kinase 1; D051057:Proto-Oncogene Proteins c-akt; D051571:Protein Kinase C-alpha