Protac synthesized on the basis of azaflavonoid derivatives possesses favorable anti-hepatocellular carcinoma activity

Hepatocellular carcinoma remains (HCC) as a global challenge as a threat to human health. Synthesized azaflavonoid derivative 2-38, which is not strongly cytotoxic to normal cells and tumor cells, and three Proteolysis-targeting chimeras (PROTACs) were synthesized by using the PROTACs coupling drug strategy, among which 2-38-III showed strong proliferation inhibitory activity against hepatocellular carcinoma cells, and further evaluated its antitumor activity and mechanism of action in hepatocellular carcinoma cells HepG2 cells. The anti-tumor activity and mechanism of action of 2-38-III in HepG2 were further evaluated. At the cellular level, it was found that compound 2-38-III could effectively inhibit the proliferation and colony formation of HepG2 cells, cell migration and vascularization of HUVEC cells. 2-38-III induced Apoptosis in HepG2 cells, with an Apoptosis rate of 45.4 %, a decrease in the mitochondrial membrane potential (MMP) of the cells, and an increase in Reactive Oxygen Species (ROS). Mechanistic studies revealed that the mitochondrial pathway and MAPK pathway were related to the induction of Apoptosis. At the animal level, 2-38-III effectively hindered the growth of tumor mass in a mouse model, with an inhibition rate of 58.48 %, and promoted Apoptosis of tumor cells. 2-38-III is a promising anti-tumor PROTAC drug with low toxicity to normal cells.

2–38-III; Apoptosis; Azaflavones; HCC; PROTACs.