D14, a β-carboline alkaloid derivative of dehydrocrenatidine, exerts anti-glioma effect by targeting SRC

Gliomas are malignant tumors of the central nervous system, which urgently require new drugs or treatment methods. It was found that dehydrocrenatidine (DEC), a β-carboline alkaloid isolated from Picrasma quassioides, had good antitumor activity, including against gliomas. This study designed the total DEC synthesis route, and the gram-level yield reached about 49%. To obtain more active β-carboline derivatives, we modified the N1 and C3/C6/C10 positions, producing nineteen compounds (D1-D19), which were screened in six glioma cell types, including three types of clinical primary cells. D14 had the best cytotoxicity, and induced significant apoptosis and oxidative stress in glioma cells. Virtual screening predicted D14 possibly targeting the proto-oncogene tyrosine-protein kinase Src (SRC) to exert an anti-tumor effect. Molecular dynamics and CETSA verified D14 binding to SRC at the site of Gln¹⁴⁷, inhibiting the phosphorylation of SRC in glioma cells. Mechanistically, D14 markedly suppressed the PI3K/AKT and STAT3 signaling pathways. D14 significantly inhibited tumor growth without functional toxicity to other normal organs in the model of orthotopically transplanted GL261 tumor cells. Post-D14 treatment in vivo p-SRC levels declined prominently. In conclusion, this study elucidated the potential mechanism of action of the β-carboline alkaloid derivative D14 against glioma and provided a theoretical and scientific basis for glioma prevention and treatment.