Design and Synthesis of N-Heteroacridone Derivatives and Their Ferroptosis-Inducing Activity Against Human Melanoma.

In order to obtain structurally unique and biologically significant antitumor compounds, a series of N-heteroacridone derivatives were designed and synthesized under the guidance of "scaffold hopping" strategy. The antiproliferative effects of the synthetic N-heteroacridones were evaluated against five tumor cell lines (Cal-27 human tongue cancer, A673 human Ewing's sarcoma, 143B human osteosarcoma, T24 human bladder cancer, and A375 human melanoma) and one normal line (HaCaT human keratinocytes), with doxorubicin (Dox) used as a positive control. The best compound 8E showed selective inhibitory effect against human melanoma A375 cells with IC50 value of 1.49 ± 0.56 μM. Interestingly, instead of acting as an apoptosis-inducing agent, 8E triggers ferroptosis in A375 cells, suggesting its potential for skin cancer therapy.