Design, synthesis and anti-tumor activation of β-carboline alkaloids derivatives from Picrasma quassioides

In this study, a series of N-9 substituted β-carboline derivatives were designed, synthesized, and further evaluated for their anti-tumor activity through an integrated approach combining network pharmacology, chemical synthesis, in vitro pharmacological assays, and molecular docking. Furthermore, the underlying mechanism of action was elucidated. Firstly, 33 kinds of β-carboline alkaloids in Picrasma quassioides were screened by TCMSP, HERB and other databases. 493 potential anti-tumor targets were obtained by target prediction and intersection analysis. Combined with GO and KEGG enrichment analysis, MAPK and NF-κB signaling pathways were determined as the core research directions. Ten β-carboline N-9 substituted derivatives were successfully synthesized from L-tryptophan by Pictet-Spengler reaction, oxidative cyclization and amide condensation reaction. The yields were 55.29% ∼ 77.39%. The results showed that compound 4  had significant anticancer activity in vitro, and its mechanism was related to the targeted regulation of MAPK and NF-κB signaling pathways. It can block the activation of NF-κB and ERK 1/2 signaling pathways by down-regulating the expression of p-p65 and p-ERK 1/2 proteins. Molecular docking results showed that compound 4 could form a stable binding conformation with p65, ERK 1 and ERK 2 target proteins through intermolecular forces such as van der Waals force and hydrogen bond, among which the binding affinity with ERK 1 was the strongest. This finding provides experimental basis and theoretical support for the development of targeted anticancer drugs derived from natural products.