Mitochondria-targeting phosphonium salts of monensin A as the source of novel antiproliferative agents

Michał Sulik, Marta Jędrzejczyk, Magdalena Mielczarek-Puta, Gwan Yong Lim, Małgorzata Podsiad, Jakub Hoser, Piotr Bednarczyk, Marta Struga, Adam Huczyński,
Mitochondria-targeting phosphonium salts of monensin A as the source of novel antiproliferative agents,
European Journal of Medicinal Chemistry Reports, Volume 14, 2025, 100275, https://doi.org/10.1016/j.ejmcr.2025.100275.
ISSN 2772-4174, (https://www.sciencedirect.com/science/article/pii/S2772417425000317)

Abstract: Monensin A is a representative of natural ionophores, which exhibit a broad spectrum of biological properties, with the most fascinating being its potent anticancer activity. A very intriguing research direction is the rational chemical modification of the monensin A skeleton to obtain analogs with higher antiproliferative activity and selectivity indices. In this paper, synthetic access to monensin A conjugates with mitochondria-targeting chemical moieties, such as the triphenylphosphonium cation and its analogs, is presented. Furthermore, the obtained derivatives were screened for lead structures with improved anticancer properties and mitochondria-targeting ability. Some of the obtained compounds exhibited greater antiproliferative activity and selectivity than unmodified monensin. Furthermore, biological and biophysical studies have confirmed that the induction of apoptosis by the aforementioned hybrids is linked to targeting of mitochondria in cancer cells. These results prove that such a strategy is a promising approach for the search for new effective drug candidates.

Keywords: Antiproliferative activity; Antibacterial activity; Triphenylphosphonium cation: TPP cation; Mitochondrial membrane potential; Black lipid membrane