Discovery of novel fluorine-containing parthenolide analogues as potential antitumor agents

Abstract

Incorporating fluorine-containing groups into the chemical skeleton is expected to enhance bioactivity and bioavailability. Directly introducing fluorine groups into the parthenolide skeleton remains challenging and limited. In this research, a series of novel fluorine-containing parthenolide derivatives were synthesized through late-stage diversification strategy. And the most promising derivate 1 exhibited good antiproliferative activity against NCI–H820 (IC₅₀: 2.66 μM), Huh-7 (IC₅₀: 2.36 μM), and PANC-1(IC₅₀: 2.16 μM). The preliminary mechanism study indicated compound 1strongly inhibited the colony formation number of NCI–H820, Huh-7 and PANC-1 cells and inhibited lung cancer metastasis with a dose-dependent manner through inhibiting STAT3 signaling pathway. Compound 16, a prodrug of compound 1, showed a significant improvement in aqueous solubility and oral bioavailability compared with parthenolide. Moreover, compound 16 significantly suppressed tumor growth in lung patient-derived tumor xenograft model without obvious toxicity. Based on the above results, we propose that compound 16 may be a promising lead compound for treatment of lung cancer.