New Sinomenine Derivative as a Potential Drug for Cervical Cancer via Inducing Ferroptosis.

Cervical cancer remains a serious threat to women's health due to chemotherapy resistance, poor prognosis, and survival rates. Novel anti-cervical cancer agents are urgently needed. Sinomenine derivatives, which were prepared from sinomenine (a natural morphinane alkaloid), have been previously reported by us to be cytotoxic toward various cancer cell lines. Also, an increase in ROS production, which is associated with ferroptosis, was observed in cancer cells. In this study, we synthesized 18 sinomenine derivatives and evaluated their antitumor activity in vitro against four human tumor cell lines (HeLa, HepG2, A549, and HT-29). Five derivatives (12-16) containing quinoline fragments showed broad-spectrum antitumor activity. Significantly, 16 showed specific activity against HeLa and HT-29 cells, with IC50 values of 5.60 and 7.60 μM, respectively. Its optimal lipophilicity (-1 < log P < 2) likely contributes to this efficacy. Further study in vitro showed that Derivative 16 could increase the accumulation of ferrous iron, which caused an increase in ROS levels and MDA contents, and a decrease in GPX4 activity. Western blot results showed that 16 decreased the FHTI-to-GAPDH, SLC7A11-to-GAPDH, and GPX4-to-GAPDH ratios. Molecular docking simulation results suggested that 16 can interact with ferroptosis-related proteins via the van der Waals force, and cation-π, anion-π, and hydrogen bonding interactions. In brief, Compound 16 may be a potentially useful drug for the treatment of cervical cancer, as it induces ferroptosis in HeLa cells by inhibiting FTH1 expression and the SLC7A11/GSH/GPX4 pathway.