Synthesis and antitumor activity of novel 2, 3-didithiocarbamate substituted naphthoquinones as inhibitors of pyruvate kinase M2 isoform |
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| Authors: | Xianling Ning Hailong Qi Ridong Li Yan Jin Michael A McNutt |
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| Institution: | 1. Institute of Systems Biomedicine, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing, China;2. Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China;3. Peking-Tsinghua Center for Life Sciences, Peking University Health Science Center, Beijing, China;4. Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China |
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| Abstract: | The M2 isoform of pyruvate kinase (PKM2) is a potential antitumor therapeutic target. In this study, we designed and synthesised a series of 2, 3-didithiocarbamate substituted naphthoquinones as PKM2 inhibitors based on the lead compound 3k that we previously reported. Among them, compound 3f (IC50?=?1.05?±?0.17 µM) and 3h (IC50?=?0.96?±?0.18 µM) exhibited potent inhibition of PKM2, and their inhibitory activities are superior to compound 3k (IC50?=?2.95?±?0.53 µM) and the known PKM2 inhibitor shikonin (IC50?=?8.82?±?2.62 µM). In addition, we evaluated in vitro antiproliferative effects of target compounds using MTS assay. Most target compounds exhibited dose-dependent cytotoxicity with IC50 values in nanomolar concentrations against HCT116, MCF7, Hela, H1299 and B16 cells. These small molecule PKM2 inhibitors not only provide candidate compounds for cancer therapy, but also offer a tool to probe the biological effects of PKM2 inhibition on cancer cells. |
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| Keywords: | M2 isoform of pyruvate kinase PKM2 inhibitors 2 3-didithiocarbamate substituted naphthoquinones antiproliferative effects |
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