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

A bioactivity repurposing strategy expanded the potential pharmacological applications of sophoridine derivatives. • Sophoridine derivatives modulated the Topo I–DNA catalytic system and exhibited preliminary antitumor activity. • Molecular simulations characterized potential interactions and dynamic behaviors within the Topo I–DNA complex. 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 IC 50 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. A series of sophoridine-based derivatives were systematically evaluated for their antitumor potential. In vitro antiproliferative assays identified compounds 5 and 9 as active candidates against A549 cells, with IC 50 values of 0.124 μM and 1.396 μM, respectively. Topo I-mediated DNA relaxation assays showed that both compounds interfered with the Topo I–DNA catalytic system in a concentration-dependent manner. Molecular docking, molecular dynamics simulations, and PMF analyses further characterized their potential interactions and dynamic behaviors within the Topo I–DNA complex. Preliminary in vivo evaluation suggested that compounds 5 and 9 exhibited inhibitory effects on tumor growth, accompanied by increased tumor necrotic changes. Collectively, these findings indicate that sophoridine derivatives possess promising antitumor potential, while modulation of the Topo I–DNA system may represent one potential mechanism contributing to their biological effects, providing a basis for further optimization and development of sophoridine-based antitumor candidates. Download: Download high-res image (333KB) Download: Download full-size image