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

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.

Ferrocenes in medicinal chemistry; a personal perspective

“…Air-and water-stable, metal-based complexes allow us to probe biological targets in ways we cannot achieve with carbon-based molecules. Metal incorporation can also alter the pharmacokinetics of a drug, benefiting from ligand-metal exchange reactions and enable unique modes of action, such as reactive oxygen species generation or photorelease, which can add to further DNA damage for example [3,4] [5]. Much of this is covered in many excellent treatises [6][7][8][9] [10].…”

Mitochondria-targeting fluorescent molecules for high efficiency cancer growth inhibition and imaging

“…It selectively accumulates in the mitochondria of cancer cells, disrupting normal function by dissipating the proton gradient across the inner mitochondrial membrane (decrease of Δ Ψ m , Scheme 1), triggering apoptosis or necrosis depending on the genetic background 18. However, F16's therapeutic efficacy has often been thought to be insufficient for drug development,19 as previous studies on structural modifications of F16 resulted in a limited improvement on their anti-cancer activity 20,21. A general opinion arose that DLCs naturally have limited anti-cancer activity because they often fail to cause large disruption of mitochondrial membrane potential (decrease of ATP production) to kill cancer cells 19,22.…”

“…However, F16's therapeutic efficacy has often been thought to be insufficient for drug development,19 as previous studies on structural modifications of F16 resulted in a limited improvement on their anti-cancer activity 20,21. A general opinion arose that DLCs naturally have limited anti-cancer activity because they often fail to cause large disruption of mitochondrial membrane potential (decrease of ATP production) to kill cancer cells 19,22. As a result, DLCs have been used simply as a cargo group to deliver functional molecules to the mitochondria selectively 19,23–25…”

Sensors, Imaging Agents, and Theranostics to Help Understand and Treat Reactive Oxygen Species Related Diseases

“…Four anticancer prodrugs have been developed by Mokhir and co‐workers, using arylboronic ester and ferrocene units. The first prodrug designed to solve a problem associated with ROS‐dependent prodrugs, where prodrug‐cleavage is inefficient at low micromolar concentrations of prodrug and ROS was achieved by the combination of an arylboronic ester and a ferrocene group .…”

“…The same group have also prepared a prodrug of carboplatin with N‐alkylamino‐ferrocene responsive to ROS, designed to specifically target the mitochondria of A2780 cancer cells with an improved anticancer activity. Using a similar concept, an H 2 O 2 ‐activatable prodrug was developed to release both the antioxidant, quinone methide (QM) (for GSH alkylation) and catalyst for additional ROS generation .…”