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In this study, we investigated the anticancer effects of FS-7, a flavonoid salicylate derivative, in human gastric carcinoma MGC-803 cell line and studied its preliminary anticancer effects. FS-7 displayed greater in vitro cytotoxicity against MGC-803 cell line compared with 5-Fu and had a certain extent of selectivity to cancer cells. The flow cytometry analysis revealed that FS-7 induced apoptosis MGC-803 cells and mainly caused cells arrest in the G2/M phase in a concentration-dependent manner. Additionally, FS-7 inhibited the colony formation and cell migration in a concentration-dependent manner. Notably, FS-7 noticeably down-regulated glycolysis-related protein HIF-1α, HK-II and PFKP expression in a concentration-dependent manner, possibly causing glycolysis inhibition. Importantly, compared with 5-Fu, FS-7 showed better anticancer activity in the MGC-803 xenograft murine tumor models. Collectively, the present study provided a promising anticancer drug candidate for gastric cancer therapy., (Copyright © 2018 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Simultaneous targeting of tumor vasculature and inhibitors of tumor cell glycolysis may be a promising antitumor strategy. Here, we reported the total synthesis and biological evaluation of A‐ring arylurea flavonoid derivatives with B‐ring trimethoxy group, which exhibited potent antitumor activity against a variety of tumor cells in vitro. Most of the derivatives showed in vitro antitumor activity on HepG‐2, HGC‐27, MDA‐MB‐231, and A549 cells. Among them, compounds 8e, 8f, 8g, 8h, 8j, and 8l also exhibited significant anti‐proliferation effects on liver tumor cell subtypes BEL‐7402 and SMMC‐7721. Compound 8l had the lowest IC50 value (5.61 ± 0.39 μM) on HepG‐2 cells, and showed the effects of inhibiting colony formation, arresting the cell cycle in G0/G1 phase, and inducing apoptosis in a concentration‐dependent manner. In addition, the toxicity of compound 8l on human normal cells LO2 and GES‐1 was lower than that of sorafenib. The inhibitory effects of compound 8l on the expression of glycolytic rate‐limiting enzymes HKII, PFK‐1, PKM2 and vascular endothelial growth factor were further evaluated. Corresponding reduction in intracellular lactate was also detected after compound 8 treatment. Our results support an antitumor strategy targeting tumor vasculature and glycolysis to discover and develop a new generation of antitumor drugs. [ABSTRACT FROM AUTHOR]

[Display omitted] Metabolism is reprogrammed in a variety of cancer cells to ensure their rapid proliferation. Cancer cells prefer to utilize glycolysis to produce energy as well as to provide large amounts of precursors for their division. In this process, cancer cells inhibit the activity of pyruvate dehydrogenase complex (PDC) by upregulating the expression of pyruvate dehydrogenase kinases (PDKs). Inhibiting the activity of PDKs in cancer cells can effectively block this metabolic transition in cancer cells, while also activating mitochondrial oxidative metabolism and promoting apoptosis of cancer cells. To this day, the study of PDKs inhibitors has become one of the research hotspots in the field of medicinal chemistry. Novel structures targeting PDKs are constantly being discovered, and some inhibitors have entered the clinical research stage. Here, we reviewed the research progress of PDKs inhibitors in recent years and classified them according to the PDKs binding sites they acted on, aiming to summarize the structural characteristics of inhibitors acting on different binding sites and explore their clinical application value. Finally, the shortcomings of some PDKs inhibitors and the further development direction of PDKs inhibitors are discussed. [ABSTRACT FROM AUTHOR]

[Display omitted] • A review of inhibitors of glycolysis rate-limiting enzyme. • The structural activity and anti-tumor mechanism of related inhibitors are described. • This review will help further research and application of glycolysis inhibitors. Tumor cells mainly provide necessary energy and substances for rapid cell growth through aerobic perglycolysis rather than oxidative phosphorylation. This phenomenon is called the "Warburg effect". The mechanism of glycolysis in tumor cells is more complicated, which is caused by the comprehensive regulation of multiple factors. Abnormal enzyme metabolism is one of the main influencing factors and inhibiting the three main rate-limiting enzymes in glycolysis is thought to be important strategy for cancer treatment. Therefore, numerous inhibitors of glycolysis rate-limiting enzyme have been developed in recent years, such as the latest HKII inhibitor and PKM2 inhibitor Pachymic acid (PA) and N-(4-(3-(3-(methylamino)-3-oxopropyl)-5-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazol-1-yl)phenyl)propiolamide. The review focuses on source, structure-activity relationship, bioecological activity and mechanism of the three main rate-limiting enzymes inhibitors, and hopes to guide the future research on the design and synthesis of rate-limiting enzyme inhibitors. [ABSTRACT FROM AUTHOR]

• Novel 5,6,7-trimethoxy flavonoid salicylate derivatives were synthesized and characterized. • Compound 7f exhibited potent anti-tumor activity in vitro. • Compound 7f was effective in reducing the stability of microtubule cytoskeleton. • Docking studies mimicked the possible binding mechanisms of compound 7f to tubulin. • 7f down-regulated lactate production and glycolysis-related proteins expression. • Compound 7f decreased HIF-1α expression under hypoxic conditions. 5,6,7-Trimethoxy flavonoid salicylate derivatives were designed by the joining of three important pharmacophores (TMP, flavonoid, and SA) according to the combination principle. A series of novel trimethoxy flavonoid salicylate derivatives were synthesized and their in vitro anti-tumor activities were evaluated. Among these derivatives, compound 7f exhibited excellent antiproliferative activity against HGC-27 cells and MGC-803 cells with IC 50 values of 10.26 ± 6.94 μM and 17.17 ± 3.03 μM, respectively. Subsequently, the effects on cell colony formation (clonogenic survival assay), cell migration (wound healing assay), cell cycle distribution (PI staining assay), cell apoptosis (Hoechst 33258 staining assay and annexin V-FITC/PI dual staining assay), lactate level (lactate measurement), microtubules disarrangement (immunofluorescence staining analysis) and docking posture (molecular docking simulation) were determined. Further western blot analysis confirmed that compound 7f could effectively down-regulate the expression of glycolysis-related proteins HIF-1α, PFKM and PKM2 and tumor angiogenesis-related proteins VEGF. Overall, these studies suggested that compound 7f , as the representative compound of those, might be a promising candidate for the treatment of gastric cancer and deserved the further studies. [ABSTRACT FROM AUTHOR]