Sinomenine derivative 1f suppresses glioblastoma through inducing both apoptosis mediated by intrinsic pathway and necroptosis mediated by TNF-α/NF-κB/MAPK signaling pathway.

Glioblastoma (GBM) is the most prevalent and aggressive primary malignant brain tumor. Currently, there is a severe lack of drugs to treat GBM. In the study, we established the configuration of novel enantiomeric compounds of sinomenine derivatives through chemical synthesis and X-ray diffraction analysis. Based on this structural characterization, we designed and synthesized a series of sinomenine derivatives and evaluated their antiproliferative activity in GBM cell lines. Among them, compound 1f exhibited notable antiproliferative activity and was amenable to large-scale synthesis. Mechanistic studies reveal that compound 1f induces mitochondria-dependent apoptosis. Furthermore, we also found that compound 1f induced necroptosis by activating the TNF-α/NF-κB/MAPK signaling pathway. Inducing dual modes of cell death is beneficial for overcoming drug resistance associated with reliance on a single death pathway. In addition, with favorable blood-brain barrier (BBB) permeability, compound 1f was found to inhibit the growth of orthotopic GBM and improve the survival rate. These results suggest that compound 1f may be a promising candidate with an excellent safety profile for the treatment of GBM.