Design, synthesis and investigation of biological activity and mechanism of fluoroaryl-substituted derivatives at the FL118 position 7.

Addition of fluorine atoms into chemical compounds is a validated strategy to enhance their physical, chemical and biological properties. In this study, FL118, a novel camptothecin-related small molecule known for its unique mechanism of action and superior antitumor efficacy, was utilized as a foundational drug platform. By replacing the hydrogen atom at position 7 of FL118 with a fluoroaryl group, a diverse array of FL118 derivatives were synthesized. Our investigations revealed that the majority of these newly synthesized compounds exhibited improved cytotoxicity compared to FL118, with some demonstrating enhanced in vivo antitumor efficacy. Among these derivatives, compound 7h stood out and was subjected to detailed analysis. Compound 7h demonstrated a remarkable ability to inhibit colorectal cancer (CRC) cell colony formation and cell migration, while also promoting reactive oxygen species (ROS) production and CRC cell apoptosis. Notably, our studies unveiled that the presence of DDX5 could modulate Topoisomerase I (Top1) activity, a process effectively reversed by a low concentration of 7h, but not SN38. Moreover, only 7h was able to decrease DDX5 expression, SN38 was not. Molecular docking studies further supported the binding of 7h to DDX5. Interestingly, although both 7h and SN38 exhibited similar inhibitory effects on Top1 activity, only 7h, and not SN38, could inhibit DDX5. These findings not only pave the way for deeper mechanistic explorations of FL118 and its derivatives in cancer research but also position the identified compound 7h as a promising candidate for further development.