Pyranobutflavin: a butoxy-bridged pyranone-flavonoid hybrid from baicalin, and its anti-hepatocellular carcinoma activity

A butoxy-bridged pyranone-flavonoid hybrid, pyranobutflavin, together with two known compounds (baicalein and baicalin butyl ester), was obtained after high-temperature-little-acid hydrolysis of baicalin naturally occurring in the roots of Scutellaria baicalensis Georgi. Cytotoxicity assays revealed that pyranobutflavin exhibited enhanced anticancer activity compared to baicalin, baicalein, and baicalin butyl ester across various cancer cell lines. Notably, its effect was most pronounced against hepatocellular carcinoma (HCC) cells, with superior selectivity indices over normal cells. Furthermore, this hybrid significantly suppressed proliferation and migration while inducing reactive oxygen species accumulation and apoptosis of HCC cells. Network pharmacology analysis revealed that the mechanism of pyranobutflavin could be closely related to PI3K-Akt and MAPK pathways. Acute toxicity testing established a safe dose (5 mg/kg, i.p.) in mice, at which pyranobutflavin validated its antitumor efficacy in HepG2 xenograft model. These findings identify pyranobutflavin as a promising selective anti-HCC derivative with enhanced therapeutic potential over its natural precursors.