Copper(II)-Mediated Mitochondria-Targeting in Cancer Cells

Körber M, Halter F, Attia D, Körber E, Tietze R, Alexiou C, Hampel F, Meyer K, Mokhir A (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Book Volume: 69

Pages Range: 16896-16910

Journal Issue: 14

DOI: 10.1021/acs.jmedchem.6c00588

Abstract

Mitochondria are attractive anticancer targets, but selective targeting remains challenging. We report a Cu²⁺-mediated strategy for mitochondria-directed activity based on intracellular metal coordination. Aminoferrocene drugs were functionalized with Cu²⁺-binding ligands to exploit elevated copper levels in cancer cells. Among these, the bipyridine conjugate AFb-L4 displays pronounced Cu²⁺-dependent cytotoxicity, with an IC50 of 29 nM in ovarian carcinoma cells (∼500-fold enhancement upon Cu²⁺ addition). Spectroscopic, magnetic, and mass spectrometric analyses confirm formation of a 1:1 AFb-L4–Cu²⁺ complex without electronic coupling between the Cu²⁺ and ferrocene centers. Intracellular Cu²⁺ coordination converts AFb-L4 into a cationic species that accumulates in mitochondria, inducing loss of membrane potential, mitochondrial remodeling, and mitochondrial ROS generation. Structure–activity relationships show that stabilization of Cu²⁺ is critical, as a sterically hindered isomer with reduced Cu²⁺ binding is largely inactive. These results establish intracellular Cu²⁺ coordination as a trigger for mitochondrial targeting.

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How to cite

APA:

Körber, M., Halter, F., Attia, D., Körber, E., Tietze, R., Alexiou, C.,... Mokhir, A. (2026). Copper(II)-Mediated Mitochondria-Targeting in Cancer Cells. Journal of Medicinal Chemistry, 69(14), 16896-16910. https://doi.org/10.1021/acs.jmedchem.6c00588

MLA:

Körber, Marlies, et al. "Copper(II)-Mediated Mitochondria-Targeting in Cancer Cells." Journal of Medicinal Chemistry 69.14 (2026): 16896-16910.

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