Mitochondrial-Targeted Triphenylphosphonium-Conjugated Ionophores with Enhanced Cytotoxicity in Cancer Cells

Michał Sulik, Marta Jędrzejczyk, Magdalena Mielczarek-Puta, Jakub Hoser, Piotr Bednarczyk, Marta Struga, Adam Huczyński, „Mitochondrial-Targeted Triphenylphosphonium-Conjugated Ionophores with Enhanced Cytotoxicity in Cancer Cells”, (2025), Molecules 30, no. 22: 4413AbstractSalinomycin and monensin represent a class of natural ionophore antibiotics with strong anticancer properties. In this paper we report on chemical modification of these compounds by conjugation with phosphonium cations for targeting conjugates to the mitochondria of cancer cells. Our findings indicate that this approach yields conjugates with enhanced anticancer activity and selectivity, outperforming not only the parent compounds but also the widely used chemotherapeutic agent, doxorubicin. Comprehensive biological and biophysical analyses proved that the conjugates target the mitochondria in cancer cells, with some of the derivatives additionally promoting generation of mitochondrial reactive oxygen species (mtROS). This targeted strategy holds significant promise for the development of effective mitochondrial-targeted novel anticancer agent. Keywords: ionophore antibiotics; salinomycin; monensin; mitochondria-targeting conjugates; antiproliferative activity; triphenylphosphonium cation