Targeting cancer cell mitochondria with a multivalent source of singlet oxygen

Abstract

Naphthalene, anthracene and pyridone endoperoxides are known to thermally release singlet oxygen. However, in the cycloreversion reaction, singlet oxygen is produced stoichiometrically; therefore, multiple singlet oxygen releasing modules are expected to be very useful in inducing apoptosis of cancer cells. Herein, we present a potential therapeutic agent presenting three-pyridone endoperoxide modules and a mitochondria targeting group. Compared to previously reported pyridone-based monofunctional endoperoxides, the triple endoperoxide is highly effective as evidenced by assays and fluorescence microscopy.

Keywords

cancer / endoperoxides / mitochondria targeting / PDT / singlet oxygen

References

[1] X. Zhao, J. Liu, J. Fan, H. Chao, X. Peng, Chem. Soc. Rev. 2021, 50, 4185.

[2] G. Gunaydin, M. E. Gedik, S. Ayan, Front. Chem. 2021, 9, 691697.

[3] H. Wu, L. Wang, Y. Wang, Y. Shao, G. Li, K. Shao, E. U. Akkaya, Angew. Chem. Int. Ed. 2022, 61, e202210249.

[4] Z. Liu, L. Wang, G. Li, R. Sun, K. Shao, H. Wu, E. U. Akkaya, Chem. Eur J. 2024, 30, e202401277.

[5] L. Wang, H. Wu, Z. Liu, R. Sun, Y. Li, Y. Si, Y. Nie, Y. Qiao, X. Qian, S. Zhang, G. Li, W. Sun, Y. Pan, E. U. Akkaya, Angew. Chem. Int. Ed. 2024, 63, e202408473.

[6] W. Wang, L. Wang, R. Sun, H. Wu, Z. Liu, X. Qian, J. Quan, E. U. Akkaya, Chem. Eur J. 2025, 31, e202500243.

[7] H. Wu, L. Wang, X. Qian, W. Wang, Y. Si, R. Sun, E. U. Akkaya, Smart Mol. 2024, 2, e20230019.

[8] Y. Si, L. Wang, H. Wu, S. Yan, Y. Wang, X. Qian, Z. Liu, E. U. Akkaya, Chem. Asian J. 2025, 20, e202401051.

[9] Y. Li, L. Wang, S. Zhang, Z. Liu, R. Sun, Y. Qiao, E. U. Akkaya, Chem. Commun. 2024, 60, 8111.

[10] G. Zhang, L. Wang, Y. Qiao, F. Zhang, R. Sun, E. U. Akkaya, Chem. Commun. 2024, 60, 12197.

[11] J. M. Aubry, C. Pierlot, J. Rigaudy, R. Schmidt, Acc. Chem. Res. 2003, 36, 668.

[12] M. Klaper, T. Linker, Chem. Eur J. 2015, 21, 8569.

[13] S. Benz, S. Notzli, J. S. Siegel, D. Eberli, H. J. Jessen, J. Med. Chem. 2013, 56, 10171.

[14] M. Matsumoto, M. Yamada, N. Watanabe, Chem. Commun. 2005, 483.

[15] K.-M. Liu, Y. Wang, F.-W. Xia, S. Feng, X.-Q. Yu, M.-Y. Wu, Smart Mol. 2025, 3, e20240060.

[16] W. Fudickar, T. Linker, J. Am. Chem. Soc. 2012, 134, 15071.

[17] S. Ayan, G. Gunaydin, N. Yesilgul-Mehmetcik, M. E. Gedik, O. Seven, E. U. Akkaya, Chem. Commun. 2020, 56, 14793.

RIGHTS & PERMISSIONS

2026 The Author(s). Smart Molecules published by John Wiley & Sons Australia, Ltd on behalf of Dalian University of Technology.