Integrated experimental and computational investigation of sophoridine derivatives reveals antitumor potential and Topo I-associated mechanisms.

Sophoridine is a quinolizidine-type natural alkaloid with favorable structural modifiability and diverse biological activities. However, the pharmacological potential of sophoridine derivatives originally optimized for insecticidal activity remains largely unexplored. Here, a bioactivity repurposing strategy was applied to investigate the antitumor potential of these derivatives. Screening across multiple cancer cell models identified A549 cells as a sensitive model, and compounds 5 and 9 were selected as active candidates with IC50 values of 0.124 μM and 1.396 μM, respectively. Topo I-mediated DNA relaxation assays showed that both compounds interfered with the activity of the Topo I-DNA catalytic system in a concentration-dependent manner. Molecular docking, molecular dynamics simulations, and PMF analyses characterized their potential interactions within the Topo I-DNA complex. Preliminary in vivo evaluation suggested inhibitory effects on tumor growth accompanied by tumor tissue necrotic changes following treatment with compounds 5 and 9. Collectively, these findings highlight the antitumor potential of sophoridine derivatives and suggest that modulation of the Topo I-DNA system may represent one potential mechanism contributing to their biological effects, providing preliminary insights for the further development of sophoridine-based anticancer candidates.