Synthesis and antitumor activity of novel 2, 3-didithiocarbamate substituted naphthoquinones as inhibitors of pyruvate kinase M2 isoform

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.

Pyruvate Kinase M2 and Cancer: The Role of PKM2 in Promoting Tumorigenesis

“…There are many small molecule inhibitors and hormones that inhibit cell proliferation by targeting PKM2 (77)(78)(79). The inhibitors, namely shikonin and its analogs, flavonoid derivatives, and 2,3-dithiocarbamate substituted naphthoquinones bind to the allosteric site of PKM2, which leads to reduced glycolysis in cancer cells (77,(80)(81)(82).…”

<p>Simultaneous Inhibition of Ornithine Decarboxylase 1 and Pyruvate Kinase M2 Exerts Synergistic Effects Against Hepatocellular Carcinoma Cells</p>

“…8 Compound 3k showed anti-proliferative activity against colorectal and cervical cancer cells. 9 However, evidence on the effect of compound 3k on HCC cells remains limited.…”

Oxidative Phosphorylation: A Target for Novel Therapeutic Strategies Against Ovarian Cancer

“…Although glucose breakdown through oxidative phosphorylation (OXPHOS) yields maximum number of ATP, curtailing the metabolism to glycolysis provides the necessary biomolecule precursors needed by the tumors to maintain a high level of proliferation [ 5 , 6 , 7 , 8 ]. Several key enzymes in the glycolytic pathway and tricarboxylic acid cycle, (pyruvate kinase M2, pyruvate dehydrogenase kinase, isocitrate dehydrogenase, succinate dehydrogenase, lactate dehydrogenase and others (representative articles include [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ]) are targets for anti-cancer drugs.…”