Design, synthesis and anticancer activity of superoxide anion-releasing beta-galactoside prodrugs

LIU Jiaxuan; YAO Xueyan; TAN Yunying; HU Jing; FU Junjie; YIN Jian

doi:10.11665/j.issn.1000-5048.2024041401

Journal of China Pharmaceutical University > 2025 > 56(3): 295-304. > DOI: 10.11665/j.issn.1000-5048.2024041401

LIU Jiaxuan, YAO Xueyan, TAN Yunying, et al. Design, synthesis and anticancer activity of superoxide anion-releasing beta-galactoside prodrugs[J]. J China Pharm Univ, 2025, 56(3): 295 − 304. DOI: 10.11665/j.issn.1000-5048.2024041401

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Design, synthesis and anticancer activity of superoxide anion-releasing beta-galactoside prodrugs

LIU Jiaxuan¹,
YAO Xueyan¹,
TAN Yunying¹,
HU Jing²,
FU Junjie^1, ,,
YIN Jian^{1, 3, ,}

1.
Ministry of Education Key Laboratory of Carbohydrate Chemistry and Biotechnology, School of Biotechnology, Jiangnan University, Wuxi 214122
2.
Wuxi School of Medicine, Jiangnan University, Wuxi 214122
3.
School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, China

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This study was supported by the National Natural Science Foundation of China (No. 22325803)

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Received Date: April 13, 2024
Revised Date: October 16, 2024
Accepted Date: October 20, 2024

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Abstract

Abstract

Four novel β-galactoside prodrugs were designed and synthesized from anthraquinones HAQ-OH and AQ-OH in an attempt to use the prodrugs to selectively release superoxide anion (O₂⁻) in cancer cells and to achieve selected anticancer activity by utilizing the Warburg effect and the elevated level of β-galactosidase in certain cancer cells. Cellular assays showed that the prodrugs Gal-HAQ and Gal-AQ selectively inhibited the proliferation and induced apoptosis of ovarian cancer OVCAR-3 cells overexpressing β-galactosidase. Using O₂⁻ fluorescent probe, it was found that in OVCAR-3 cells Gal-HAQ and Gal-AQ could time-dependently release O₂⁻, which was essential for their anticancer activity. Furthermore, it was found that Gal-HAQ and Gal-AQ were effective senolytics toward senescent cells overexpressing β-galactosidase without affecting the viability of corresponding non-senescent cells, further confirming the β-galactosidase-dependent cytotoxicity of the prodrugs. In conclusion, Gal-HAQ and Gal-AQ, which release O₂⁻ in response to β-galactosidase, are expected to serve as candidate prodrugs targeting cancer cells.
- superoxide anion,
- β-galactoside prodrugs,
- anticancer drugs

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References

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Design, synthesis and anticancer activity of superoxide anion-releasing beta-galactoside prodrugs