Design, synthesis, and pharmacological evaluation of terrein derivatives targeting hepatocellular carcinoma

Hepatocellular carcinoma is a malignant tumor that ranks sixth in incidence and third in mortality globally. In this study, based on the principles of chemical splicing and prodrug synthesis strategies, a total of 26 new derivatives, including 17 cinnamic acid derivatives, 8 quinoline derivatives, and 1 triazole derivative, were designed and synthesized using terrein (1), isolated from the endophytic fungus Aspergillus terreus of Sphagneticola trilobata as the parent compound. Among these, the IC₅₀ values for the proliferation-inhibitory effects of the cinnamic acid derivative 1i and the quinoline derivative 2a on liver cancer cells Hep G2 were 0.8 and 4.6 μM, respectively, which were 120 and 21-fold stronger than those of 1. In addition, 1i and 2a exhibited proliferation inhibition rates against Hep G2 cells were observed to be lower by factors of 14.4 and 9.65, respectively, compared to those against AML-12 cells, demonstrating that moderate selectivity and a certain therapeutic window are exhibited by these compounds. Molecular mechanism studies have shown that both 1i and 2a could induce apoptosis in Hep G2 cells by inhibiting the PI3K/Akt signaling pathway, arresting the cell cycle, and suppressing cell proliferation and migration. The difference is that 1i arrested the cell cycle in the S phase, while 2a arrested it in the G0/G1 phase. Further transcriptomic analysis, combined with molecular docking and isothermal titration calorimetry results, indicated that the likely target of 1i was NCF2, while the target of 2a was WNT9A. In vivo studies further confirmed that 1i demonstrated superior anti-tumor activity and safety compared to positive control Sorafenib. Overall, the findings of this study indicate that derivatives 1i and 2a are highly promising candidate drugs for the treatment of hepatocellular carcinoma.