Discovery of mangiferin lipophilic amide derivatives as novel fatty acid synthase inhibitors with potent anti-hepatocellular carcinoma activity

Fatty acid synthase (FASN), which is highly expressed in multiple cancers, contributes critically to Cancer cell survival, proliferation, and metastasis, rendering it a promising target for therapeutic intervention. To develop novel and efficient FASN inhibitors, a series of lipophilic amide fragments were introduced into the natural inhibitor mangiferin (MGF) to synthesize new MGF derivatives. Among these derivatives, compound 4 demonstrated notable antiproliferative activity against human hepatocellular carcinoma cell lines with high FASN expression. In particular, 4 exhibited the most potent activity against Hep-G2 cells (IC₅₀ = 0.47 ± 0.06 μM), demonstrating 185-fold greater potency than MGF (IC₅₀ = 87.24 ± 2.06 μM). The capability to bind to FASN and inhibit its activity was significantly stronger than that of MGF. Further investigations revealed that 4 was involved in blocking the activation of PI3K/Akt pathway, thereby inducing Reactive Oxygen Species production and promoting Cancer cells Apoptosis. Moreover, 4 exhibited a high selectivity index toward Hep-G2 cells (SI = 260.00) and inhibited the migration and invasion of Hep-G2 cells. These findings may serve as a valuable reference for the development of novel FASN inhibitors exhibiting potent anti-hepatocellular carcinoma activity.