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Here, we reported the total synthesis and biological evaluation of A\u2010ring arylurea flavonoid derivatives with B\u2010ring 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\u20102, HGC\u201027, MDA\u2010MB\u2010231, and A549 cells. Among them, compounds <jats:bold>8e, 8f, 8g, 8h, 8j<\/jats:bold>, and <jats:bold>8l<\/jats:bold> also exhibited significant anti\u2010proliferation effects on liver tumor cell subtypes BEL\u20107402 and SMMC\u20107721. Compound <jats:bold>8l<\/jats:bold> had the lowest IC<jats:sub>50<\/jats:sub> value (5.61\u2009\u00b1\u20090.39\u2009\u03bcM) on HepG\u20102 cells, and showed the effects of inhibiting colony formation, arresting the cell cycle in G<jats:sub>0<\/jats:sub>\/G<jats:sub>1<\/jats:sub> phase, and inducing apoptosis in a concentration\u2010dependent manner. In addition, the toxicity of compound <jats:bold>8l<\/jats:bold> on human normal cells LO2 and GES\u20101 was lower than that of sorafenib. The inhibitory effects of compound <jats:bold>8l<\/jats:bold> on the expression of glycolytic rate\u2010limiting enzymes HKII, PFK\u20101, PKM2 and vascular endothelial growth factor\u00a0were 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.<\/jats:p>","DOI":"10.1002\/ddr.22035","type":"journal-article","created":{"date-parts":[[2023,1,24]],"date-time":"2023-01-24T23:39:50Z","timestamp":1674603590000},"page":"448-464","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Design, synthesis, and antitumor evaluation of trimethoxyflavonoid with arylurea structure against hepatocellular carcinoma"],"prefix":"10.1002","volume":"84","author":[{"given":"Xueyan","family":"Sun","sequence":"first","affiliation":[{"name":"Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research HengYang Medicial School  Hengyang Hunan 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