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

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. • Novel phosphonium salts of monensin A ( MON ) are obtained. • Some of MON derivatives exhibit higher antiproliferative activity and higher selectivity than unmodified MON. • Unmodified MON did not change the oxygen respiration rate of A549 cells while its derivatives did induce changes in oxygen respiration. • Our studies prove that the anticancer activity of phosphonium salts of monensin A is linked to the targeting of mitochondria.