Design, Synthesis, and Biological Evaluation of Novel, Fluorinated Camptothecin Derivatives as Potential Topoisomerase I Inhibitors.

Camptothecin (CPT), a classical topoisomerase I (TOP I) inhibitor, shows potent antitumor activity but is limited by toxicity and lactone instability. Herein, structural optimization of the CPT scaffold was conducted via A-ring fluorination and C-7 and C-17 modifications. A series of fluorinated derivatives were synthesized and evaluated for antiproliferative activity. Structure-activity relationship studies identified C-11 fluorination as optimal, whereas C-7 ethyl and C-17 thiocarbonyl substitutions enhanced potency. Compounds W3 (11F-CPT) and W12 (7Et-11F-CPT) exhibited potential inhibitory effects against pancreatic cancer cells (PANC-1 and BxPC-3) and were selected for further study. Both compounds demonstrated potent antitumor activity in vitro and in vivo with improved stability and safety. Mechanistic studies have indicated that they induce cell cycle arrest and apoptosis and inhibit TOP I activity. These findings clarify the effects of fluorination on CPT activity and support its potential use in pancreatic cancer, thereby providing guidance for scaffold optimization.