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ROS‐Responsive N‐Alkylaminoferrocenes for Cancer‐Cell‐Specific Targeting of Mitochondria

2018; Wiley; Volume: 57; Issue: 37 Linguagem: Inglês

10.1002/anie.201805955

1521-3773

Viktor Reshetnikov, Steffen Daum, Christina Janko, Weronika Karawacka, Rainer Tietze, Christoph Alexiou, Solomiya Paryzhak, Tetiana Dumych, Rostyslav Bilyy, Philipp Tripal, Benjamin Schmid, Ralf Palmisano, Andriy Mokhir,

Organometallic Complex Synthesis and Catalysis

Abstract Mitochondrial membrane potential is more negative in cancer cells than in normal cells, allowing cancer targeting by delocalized lipophilic cations (DLCs). However, as the difference is rather small, these drugs affect also normal cells. Now a concept of pro‐DLCs is proposed based on an N‐alkylaminoferrocene structure. These prodrugs are activated by the reaction with reactive oxygen species (ROS) forming ferrocenium‐based DLCs. Since ROS are overproduced in cancer, the high‐efficiency cancer‐cell‐specific targeting of mitochondria could be achieved as demonstrated by fluorescence microscopy in combination with two fluorogenic pro‐DLCs in vitro and in vivo. We prepared a conjugate of another pro‐DLC with a clinically approved drug carboplatin and confirmed that its accumulation in mitochondria was higher than that of the free drug. This was reflected in the substantially higher anticancer effect of the conjugate.