Design, synthesis, and antitumor evaluation of sophoridine derivatives as topoisomerase I inhibitors based on the topomer CoMFA model

Topoisomerase I (Top I) plays a pivotal role in resolving DNA supercoiling during replication and transcription, highlighting its significance as a therapeutic target in oncology. Despite the clinical efficacy of inhibitors such as Irinotecan and Topotecan, their clinical utility is hindered by the emergence of resistance mechanisms. Sophoridine, a natural alkaloid, has demonstrated promising Top I inhibitory activity, with its derivatives showing enhanced antitumor effects. In this study, the Topomer CoMFA approach was utilized to construct a validated 3D-QSAR model to explore the structure-activity relationships (SAR) of sophoridine derivatives. Based on the model's guidance, nine derivatives were designed, four of which were synthesized and subjected to biological evaluation. Computational investigations, including molecular docking, molecular dynamics simulations, and ADMET predictions, provided detailed insights into their binding interactions and drug-like properties. These findings establish a robust theoretical framework for the rational design of sophoridine-based Top I inhibitors with potential applications in cancer treatment.