Design, synthesis, and antitumor evaluation of trimethoxyflavonoid with arylurea structure against hepatocellular carcinoma.

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]