期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 28, 期 21, 页码 3441-3445出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2018.09.026
关键词
Pyruvate dehydrogenase kinase; Pyruvate dehydrogenase complex; Antiproliferative activity; Dichloroacetophenone; Kinase inhibition
资金
- Science and Technology Development Fund, Macao S.A.R. (FDCT) [0057/2018/A2]
Dichloroacetophenone is a pyruvate dehydrogenase kinase 1 (PDK1) inhibitor with suboptimal kinase selectivity. Herein, we report the synthesis and biological evaluation of a series of novel dichloroacetophenones. Structure-activity relationship analyses (SARs) enabled us to identify three potent compounds, namely 54, 55, and 64, which inhibited PDK1 function, activated pyruvate dehydrogenase complex, and reduced the proliferation of NCI-H1975 cells. Mitochondrial bioenergetics assay suggested that 54, 55, and 64 enhanced the oxidative phosphorylation in cancer cells, which might contribute to the observed anti-proliferation effects. Collectively, these results suggested that 54, 55, and 64 could be promising compounds for the development of potent PDK1 inhibitors.
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