7 I, a structurally modified sinomenine, exerts dual anti-GBM effects by inhibiting glioblastoma proliferation and inducing necroptosis which further mediates lysosomal cell death.

Glioblastoma multiforme (GBM) is an aggressive brain tumour which drug treatment has no overall significant effect on survival rate. Sinomenine is a natural product extracted from the traditional Chinese medicine Qingteng and was found to have a certain anti-tumour effect. Although, its short biological half-life, unstable physicochemical properties, large dosage and causes histamine release have hindered its use but it may form the basis for novel drug therapy of GBM. We designed, synthesised and screened sinomenine derivative-7 I with high anti-GBM activity and investigated its mechanism of action. Its actions on GBM cells were detected by cell viability assay, RNA-Seq, Western blot, transmission electron microscopy, immunofluorescence along with other methods described. 7 I exerted anti-GBM effects through a dual mechanism. 7 I arrested the cell cycle of GBM cells at the G2/M phase by the activation of the P53/P21/CDK1/cyclin B pathway, inhibiting GBM cells proliferation. Secondly, 7 I induced necroptosis of GBM cells through the classical RIPK1/RIPK3/MLKL-dependent pathway causing lysosomal damage and membrane permeabilization leading to lysosomal-mediated cell death. Finally, in vivo xenograft experiments, 7 I significantly inhibited the growth of glioblastoma, effectively reducing inflammation in mice and showing good safety profile. 7 I, a structurally modified sinomenine, has excellent in vitro and in vivo anti-GBM activity and exerts dual anti-GBM effects by inhibiting glioblastoma proliferation and inducing necroptosis, which further mediates lysosomal cell death. In summary, 7 I is a promising candidate agent for GBM treatment.