8r(Qingdao University of Science and Technology)

In this study, a series of novel indeno[2,1-g]pteridine sulfonate derivatives are designed and synthesized. These compounds integrate the DNA-binding affinity of the pteridine ring with the covalent crosslinking ability of sulfonate moieties, aiming to induce multi-modal DNA damage. Scaffold optimization focuses on tuning the linker flexibility to spatially balance the intercalation depth of the pteridine moiety and the alkylating reactivity of the sulfonate group. Among them, 8q and 8r possess the strongest antiproliferative activities against A549 and HeLa cell lines. The interactions with DNA are investigated, and the results support their potential as DNA-damaging agents. Intracellular ROS levels in A549 cells are elevated by 8q and 8r, thus inducing oxidative damage to tumor cells. Molecular docking studies indicate that 8q and 8r have the strongest binding affinities to DNA and DNA-Topo II complex, consistent with their superior antiproliferative activities. Molecular dynamics simulations further support the theoretical basis for Topo II inhibition, and the experimental results demonstrate that the inhibitory effects of 8q and 8r on Topo II are comparable to that of mitonafide. Preliminary electrochemical studies are conducted to explore their possible metabolic pathways, suggesting that the redox processes involve reversible redox of the pteridine moiety and irreversible reduction of the indanone carbonyl group. Additionally, compared with busulfan, 8q and 8r possess markedly extended metabolic elimination times, which may allow reduced dosing frequency and improved bioavailability in practical applications.