Dichloroacetophenones targeting at pyruvate dehydrogenase kinase 1 with improved selectivity and antiproliferative activity: Synthesis and structure-activity relationships |
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Authors: | Shao-Lin Zhang Zheng Yang Xiaohui Hu Kin Yip Tam |
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Affiliation: | 1. Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau, China;2. Drug Development Core, Faculty of Health Sciences, University of Macau, Taipa, Macau, China |
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Abstract: | 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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Keywords: | Pyruvate dehydrogenase kinase Pyruvate dehydrogenase complex Antiproliferative activity Dichloroacetophenone Kinase inhibition |
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