Semi‐Synthesis of Flavonoid Glycosides and Their Anti‐Inflammatory and Antitumor Activities towards Triple Negative Breast Cancer

• Published in: Chemistry & biodiversity 2023-02, Vol.20 (2), p.e202200899-n/a
• Main Authors: Xie, Ji‐Zhao, Xu, Huan‐Ji, Zhang, Qing, Wu, Zheng, Wu, Xin‐Duo, Li, Xue‐Hua, Tan, Zhen‐Yuan, Xie, Yun‐Feng, Qiu, Li
• Format: Article
• Language: English
• Subjects: Animals; anti-inflammatory; Anti-Inflammatory Agents - pharmacology; Anticancer properties; antitumor; Biocompatibility; Biological activity; Breast cancer; Condensates; Cytotoxicity; Deacetylation; Dehydrogenation; Flavone glycosides; Flavonoids; Flavonoids - chemistry; Glycosides; Glycosides - pharmacology; hesperetin; Hesperidin; Humans; Inflammation; Interleukin 6; Interleukin-6 - metabolism; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Macrophages; Mice; Nitric Oxide; NMR; Nuclear magnetic resonance; Semisynthesis; Synthesis; Toxicity; Triple Negative Breast Neoplasms; Tumor necrosis factor; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF
• ISSN: 1612-1872; 1612-1880
• DOI: 10.1002/cbdv.202200899

Background: Flavonoid glycosides are known to possess diverse bioactivities including antitumor and anti‐inflammatory properties. Hesperetin is abundant in nature and can be used to synthesize bioactive flavonoids. This has the advantages of low cost, short synthetic steps, simple operation, and good yields. Objective: In this study, we aimed to synthesize bioactive flavonoids and flavonoid glycosides from hesperetin and evaluate the antitumor and anti‐inflammatory activities of these compounds. Methods: A series of flavonoids and their derivatives were synthesized by methoxylation, oxidative dehydrogenation, benzylation, debenzylation, and deacetylation as well as using a modified peroxyacetone method and a glycoside condensation reaction. Their anti‐inflammatory activities were evaluated for their inhibitory effects on nitric oxide (NO), tumor necrosis factor (TNF‐α), and interleukin‐6 (IL‐6) production in LPS‐induced RAW264.7 mouse macrophages. Their structures were characterized by HRMS, 1H‐NMR, and 13C‐NMR, and their cytotoxicity on the human triple‐negative breast cancer cell (TNBC) line, SUM 149, was tested by using the MST assay. Results: Most of the compounds markedly reduced NO production in LPS‐stimulated murine macrophages at the tested concentrations in a dose‐dependent manner. Among these, compounds 1, 7, 9, and 17 showed significant anti‐inflammatory activities against NO production in LPS‐induced RAW264.7 mouse macrophages. In addition, they could also reduce the release of TNF‐α and IL‐6 in a concentration‐dependent manner. Most of the tested compounds showed remarkable anti‐human TNBC activities. Compounds 1b–1m, 1, and 3 showed a certain degree of growth inhibition effect on the human TNBC cell lines and their IC50 values were all below 16.61 μM. In addition, compound 1l was the most cytotoxic with IC50 values of 1.38±0.31 μM, while the other compounds were inactive with inhibition rates