Naphthalimide-nitrosourea derivatives as dual-function antitumor agents for exploration of their action mechanisms...

In this study, a series of novel naphthalimide-nitrosourea derivatives (A-1-A-3) were synthesized as potential antitumor agents. In vitro antiproliferative activity assays demonstrated that A-1-A-3 displayed markedly enhanced inhibitory activity against HepG2 (15.98-24.32 μg/mL) and HeLa (8.54-19.03 μg/mL) cell lines, significantly outperforming the reference drug mitonafide. Mechanistic studies revealed that these derivatives exert their effects through DNA intercalation, topoisomerase II inhibition, and elevated ROS generation. Electrochemical studies indicated that A-1-A-3 undergo degradation in neutral or alkaline conditions to yield hydroxyethyl-substituted naphthalimides. Concurrently, the nitrosourea moiety generates a reactive carbocation capable of DNA alkylation and crosslinking. This dual mechanism, DNA intercalation by the naphthalimide ring and alkylation by the nitrosourea group, produces a strong synergistic antitumor effect. Additionally, a DNA oxidative damage pathway was confirmed, which demonstrated high anti-interference capacity and practical applicability in serum samples. Collectively, these findings highlight A-1-A-3 as promising multifunctional antitumor candidates with distinct structural and mechanistic advantages.