Design, synthesis, and biological evaluation of novel selenium-matrine hybrid compounds as topo I -targeted anticancer agents

The natural product matrine remains one of the most widely utilized scaffolds in drug discovery and development. Numerous reported derivatives have demonstrated potent Topoisomerase inhibitory activity along with promising Anticancer effects. Selenium, an essential trace element in living organisms, plays critical physiological roles. Emerging evidence suggests that incorporation of selenium atoms into Anticancer agents can substantially enhance their biological potency, positioning this approach as an innovative and effective strategy in modern Anticancer drug design. In the present study, we rationally designed and synthesized two series of 30 novel selenium-matrine hybrid compounds by strategically introducing selected selenium-containing functionalities (-SeCN or -SeCF₃) into the matrine skeleton. Among these hybrids, compounds 5l and 5n exhibited particularly strong inhibition of Cancer cell proliferation and migration, accompanied by significant Topoisomerase I (Topo I) inhibitory activity. Mechanistic investigations revealed that 5l and 5n induce DNA damage and elevate intracellular ROS, leading to mitochondrial dysfunction, G1-phase cell cycle arrest, and Apoptosis. Molecular docking studies combined with molecular dynamics simulations further confirmed that both compounds form stable and favorable interactions with the Topo I-DNA complex. Additionally, a preliminary evaluation of the physicochemical properties of the lead compound was performed through in silico prediction of relevant physical and chemical parameters. Acute toxicity assessments and histopathological examinations demonstrated that 5n possesses acceptable in vivo safety profiles. Collectively, these findings establish a solid theoretical and experimental foundation for the future optimization of related derivatives and their advancement into further preclinical development.