Developing dual-responsive quinolinium prodrugs of 8-hydroxyquinoline by harnessing the dual chelating sites.

The bidentate metal ion chelator 8-hydroxyquinoline (8-HQ) demonstrates significant potential in anticancer therapy but is hindered by adverse effects due to nonspecific chelation in normal tissues. The phenolic hydroxyl oxygen of 8-HQ has been extensively exploited to develop O-masked 8-HQ prodrugs aimed at achieving on-demand chelation. However, the equally crucial quinoline nitrogen for chelation remains underutilized. By alkylating the quinoline nitrogen of 8-HQ, we synthesized a series of N-masked quinolinium (QUM) prodrugs that release 8-HQ upon activation by various stimuli. Comprehensive in vitro and in vivo studies were conducted with QUM-1 and QUM-4, which are activated by HO and β-glucosidase, respectively. Both QUM-1 and QUM-4 exhibit improved cancer cell selectivity compared to 8-HQ or the O-masked isomeric prodrug, attributed to unique properties such as enhanced mitochondrial targeting and increased glucose transporter-mediated cellular uptake. Additionally, by leveraging both chelating sites, we constructed dual-masked 8-HQ prodrugs that are activated non-sequentially by two stimuli to release 8-HQ. QUM-5 demonstrates anticancer activity upon activation by UV/HO and shows improved safety in mice compared to 8-HQ. Our research presents novel applications for the construction of quaternary ammonium prodrugs utilizing aromatic tertiary amines and underscores the potential of dual-responsive prochelators for targeted cancer therapy.