Integration of a Diselenide Unit Generates Fluorogenic Camptothecin Prodrugs with Improved Cytotoxicity to Cancer Cells
| Autor: | Bingbing Chang, Miao Zhong, Jintao Zhao, Qianhe Xu, Xinming Li, Zihua Wang, Jianguo Fang |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Apoptosis Diselenide Mice chemistry.chemical_compound In vivo Drug Discovery medicine Animals Humans Prodrugs heterocyclic compounds Selenium Compounds Cytotoxicity neoplasms Cell Proliferation Fluorescent Dyes Mice Inbred BALB C Superoxide Dismutase Superoxide Optical Imaging Selenol Hep G2 Cells Glutathione Prodrug Antineoplastic Agents Phytogenic Xenograft Model Antitumor Assays Combinatorial chemistry Oxidative Stress chemistry Molecular Medicine Camptothecin Drug Screening Assays Antitumor Topoisomerase I Inhibitors medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 64:17979-17991 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.1c01362 |
| Popis: | A diselenide/disulfide unit was introduced into camptothecin (CPT), and two selenoprodrugs (e.g., CPT-Se3 and CPT-Se4) were identified to show improved potency in killing cancer cells and inhibiting tumor growth in vivo. Interestingly, the intrinsic fluorescence of CPT was severely quenched by the diselenide bond. Both the selenoprodrugs were activated by glutathione with a nearly complete recovery of CPT's fluorescence. The activation of prodrugs was accompanied by the production of selenol intermediates, which catalyzed the constant conversion of glutathione and oxygen to oxidized glutathione and superoxides. The diselenide unit is widely employed in constructing thiol-responsive materials. However, the selenol intermediates were largely ignored in the activation process prior to this study. Our work verified that integration of the diselenide unit may further enhance the parent drug's efficacy. Also, the discovery of the fluorescence quenching property of the diselenide/disulfide bond further shed light on constructing novel theranostic agents. |
| Databáze: | OpenAIRE |
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