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

Xueyan Yao; Junjiao Wang; Jie Liu; Chunjing Yu; Jing Hu; Xue Wang; Junjie Fu; Jian Yin

doi:10.1016/j.ejmech.2024.117196

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

Eur J Med Chem. 2024 Dec 20:284:117196. doi: 10.1016/j.ejmech.2024.117196. Online ahead of print.

Authors

Xueyan Yao¹, Junjiao Wang¹, Jie Liu¹, Chunjing Yu², Jing Hu³, Xue Wang⁴, Junjie Fu⁵, Jian Yin⁶

Affiliations

¹ Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology & School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, 214122, China.
² Department of Nuclear Medicine, Affiliated Hospital of Jiangnan University, Wuxi, 214122, China.
³ Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, China.
⁴ Department of Pharmacy, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, 102218, China.
⁵ Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology & School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, 214122, China; Department of Nuclear Medicine, Affiliated Hospital of Jiangnan University, Wuxi, 214122, China; Innovation Center for Vaccine Engineering, Jiangnan University, Wuxi, 214122, China. Electronic address: jfu@jiangnan.edu.cn.
⁶ Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology & School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, 214122, China; Innovation Center for Vaccine Engineering, Jiangnan University, Wuxi, 214122, China. Electronic address: jianyin@jiangnan.edu.cn.

PMID: 39721291
DOI: 10.1016/j.ejmech.2024.117196

Abstract

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 H₂O₂ 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/H₂O₂ 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.

Keywords: 8-Hydroxyquinoline; Anticancer prodrugs; Glucoside prodrugs; Metal chelators; Quaternary ammonium.