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Synthesis and biological evaluation of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionamides as pyruvate dehydrogenase kinase 1 (PDK1) inhibitors to reduce the growth of cancer cells
Zhang S.-L.; Zhang W.; Yang Z.; Hu X.; Tam K.Y.
2017-12-15
Source PublicationEuropean Journal of Pharmaceutical Sciences
ISSN18790720 09280987
Volume110Pages:87-92
AbstractMost cancer cells exhibit a high rate of glycolysis and reduced capacity in mitochondrial oxidative phosphorylation. The expression of pyruvate dehydrogenase kinases (PDKs) was found to be increased in many cancer cells. Inhibition of PDKs increases the oxidative phosphorylation of glucose, which may disrupt the balance between the demand and supply of oxygen in cancer cell, thus leading to cell death. Several reports suggested that compounds containing (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionamide group could inhibit PDKs in pyruvate dehydrogenase primary enzymatic assay. However, none of them were capable of reducing the growth of cancer cells. Herein, we report the synthesis and biological evaluation of some novel PDK1 inhibitors containing the (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionamide warhead. Excitingly, these novel PDK1 inhibitors exhibited good potency to reduce the growth of cancer cells. We have demonstrated that these compounds could physically associate with PDK1 and activate pyruvate dehydrogenase in low micromolar levels.
KeywordAnti-proliferation Binding affinity Pyruvate dehydrogenase complex Pyruvate dehydrogenase kinase
DOI10.1016/j.ejps.2017.03.030
URLView the original
Language英語
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Cited Times [WOS]:3   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
AffiliationUniversidade de Macau
Recommended Citation
GB/T 7714
Zhang S.-L.,Zhang W.,Yang Z.,et al. Synthesis and biological evaluation of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionamides as pyruvate dehydrogenase kinase 1 (PDK1) inhibitors to reduce the growth of cancer cells[J]. European Journal of Pharmaceutical Sciences,2017,110:87-92.
APA Zhang S.-L.,Zhang W.,Yang Z.,Hu X.,&Tam K.Y..(2017).Synthesis and biological evaluation of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionamides as pyruvate dehydrogenase kinase 1 (PDK1) inhibitors to reduce the growth of cancer cells.European Journal of Pharmaceutical Sciences,110,87-92.
MLA Zhang S.-L.,et al."Synthesis and biological evaluation of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionamides as pyruvate dehydrogenase kinase 1 (PDK1) inhibitors to reduce the growth of cancer cells".European Journal of Pharmaceutical Sciences 110(2017):87-92.
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