Glycosidase-activated prodrugs of a cytotoxic iron chelator for targeted cancer therapy

Debashish Tomar; Axel Steinbrueck; Adam C. Sedgwick; Matthew S. Levine; Jonathan L. Sessler; Nils Metzler-Nolte

doi:10.1039/D5MD00232J

Glycosidase-activated prodrugs of a cytotoxic iron chelator for targeted cancer therapy†

Debashish Tomar,^a Axel Steinbrueck,

^ac Adam C. Sedgwick,

^b Matthew S. Levine,

^c Jonathan L. Sessler

^c and Nils Metzler-Nolte

*^a

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* Corresponding authors

^a Faculty of Chemistry and Biochemistry, Inorganic Chemistry I – Bioinorganic chemistry, Ruhr-University Bochum, Universitaetsstrasse 150, 44801 Bochum, Germany
E-mail: nils.metzler-nolte@ruhr-uni-bochum.de

^b Department of Chemistry, King's College London, 7 Trinity Street, London, UK

^c Department of Chemistry, University of Texas at Austin, 105 E 24th street A5300, Austin, TX 78712-1224, USA

Abstract

New glycoside-prodrugs based on the iron chelator deferasirox were designed. Selective enzymatic activation by glycosidases was observed within 24 hours, accompanied by cancer cell-selective cytotoxicity. Notably, derivative 3a, bearing a β-D-galactose moiety, showed promising selective activity against galactosidase overexpressing OvCar-3 cells (IC₅₀ 9.1 ± 1.6 μM) while maintaining low activity against fibroblast control GM5756 cells (IC₅₀ > 100 μM).

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DOI: https://doi.org/10.1039/D5MD00232J
Article type: Research Article
Submitted: 14 Mar 2025
Accepted: 25 May 2025
First published: 19 Jun 2025
This article is Open Access

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RSC Med. Chem., 2025, Advance Article

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Glycosidase-activated prodrugs of a cytotoxic iron chelator for targeted cancer therapy

D. Tomar, A. Steinbrueck, A. C. Sedgwick, M. S. Levine, J. L. Sessler and N. Metzler-Nolte, RSC Med. Chem., 2025, Advance Article , DOI: 10.1039/D5MD00232J

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

RSC Medicinal Chemistry

Glycosidase-activated prodrugs of a cytotoxic iron chelator for targeted cancer therapy†

Abstract

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Glycosidase-activated prodrugs of a cytotoxic iron chelator for targeted cancer therapy

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