Novel N-Substituted Sophoridine Derivatives: Design, QSAR, Synthesis and Anticancer Activities

Abstract Sophoridine, which is derived from the Leguminous plant Sophora alopecuroides L., has certain pharmacological activity as a new anticancer drug. Herein, a series of novel N-substituted sophoridine derivatives were designed and synthesized. 2D and 3D-QSAR anticancer activity prediction models of the sophoridine derivatives were established to predict the IC50 values of the 28 designed compounds, and the results showed that the introduction of appropriate substituents on the nitrogen atom at the 12-position of sophoridinic acid may enhance their anticancer activities. The structures of 28 novel N-substituted sophoridine derivatives were confirmed by 1H nuclear magnetic resonance, 13C nuclear magnetic resonance and mass spectrometry, and their anticancer activities against four human tumor cell lines (A549, CNE-2, HepG-2, and HEC-1-B) were evaluated by MTT assay. In particular, Compound 26 presented the most significant inhibitory activity, with an IC50 of 15.6 μM against HepG-2 cells, indicating that it has potential anticancer activity. Cell cycle analysis with 26 showed that this designed sophoridine derivative could arrest cells in G0/G1 phase. This study provides a new pathway for the structural modification of this class of compounds and the research and development of anticancer drugs.