Bioactive sesquiterpene lactones from Elephantopus scaber: semi-synthesis, target fishing, anti-malignant glioma efficacy in vitro and in vivo

Traditional Chinese Medicine (TCM) offers distinct advantages in the treatment of tumors, since it serves dually as both a medicinal treatment and a dietary therapy. Elephantopus scaber (E. scaber), with a plethora of folk medicinal usage for treating pneumonia and hepatitis, contains sesquiterpene lactone (SL) as the primary component for therapeutic efficacy. The orphan drug ACT001, as the SL derivative, has been used in the treatment of glioma, which demonstrated significant potential for the development of such compounds. In this work, two series of plant-derived SL derivatives were synthesized and their efficacy against malignant glioma (MG) was evaluated. Among them, compound 1e exhibited the most potent inhibitory effects with IC₅₀ values of 3.95 and 3.43 μM against U87 and T98G cells, respectively. Preliminary mechanism investigations suggested that 1e induced the cell-cycle arrest at S phase and inhibited the tube formation to the anti-angiogenesis. Meanwhile, 1e enhanced E-cadherin protein level while decreased the levels of Vimentin, MMP-2 and MMP9, thereby suppressing MG cells migration and invasion. Furthermore, the orthotopic glioma model using live animal fluorescence imaging demonstrated the therapeutic effect of 1e on MG in vivo and pharmacokinetic studies indicated 1e with a favorable pharmacokinetic profile. Moreover, we performed competitive activity-based protein profiling (ABPP) to explore the potential targets of SL derivatives in U87 cells, providing a basis for the follow-up studies of MG.