Lysosome‐Targeting Amplifiers of Reactive Oxygen Species as Anticancer Prodrugs

Abstract

Cancer cells produce elevated levels of reactive oxygen species, which has been used to design cancer specific prodrugs. Their activation relies on at least a bimolecular process, in which a prodrug reacts with ROS. However, at low micromolar concentrations of the prodrugs and ROS, the activation is usually inefficient. Herein, we propose and validate a potentially general approach for solving this intrinsic problem of ROS‐dependent prodrugs. In particular, known prodrug 4‐(N‐ferrocenyl‐N‐benzylaminocarbonyloxymethyl)phenylboronic acid pinacol ester was converted into its lysosome‐specific analogue. Since lysosomes contain a higher concentration of active ROS than the cytoplasm, activation of the prodrug was facilitated with respect to the parent compound. Moreover, it was found to exhibit high anticancer activity in a variety of cancer cell lines (IC50=3.5–7.2 μm) and in vivo (40 mg kg−1, NK/Ly murine model) but remained weakly toxic towards non‐malignant cells (IC50=15–30 μm).

Radiosynthesis of an 18F‐fluoroglycosylated aminoferrocene for in‐vivo imaging of reactive oxygen species activity by PET

“…In our previous work, we have shown that N‐alkylaminoferrocene‐based prodrugs react with ROS in cancer cells with formation of ferrocenium species (Figure ). In particular, the first chemical reaction in this case is cleavage of the B–C bond with formation of a phenol derivative (Figure 1, “intermediate I”).…”

“…The latter is a strong reducing agent, which in cells is oxidised by ROS or even molecular oxygen with formation of N‐alkylaminoferrocenium cations (Figure 1, “Drug”). Depending on substituents, these are trapped in lysosomes or mitochondria…”

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 prodrug synthesized contained a lysosome‐targeting group with a fluorogenic coumarin unit whose fluorescence can be activated by intracellular 1 O 2 , thus enabling real‐time monitoring of drug release ( Figure ).…”

“…Structures of two lysosome‐specific prodrugs with or without theranostic function and their activating processes in cancer cells due to ROS. Reproduced with permission . Copyright 2017, Wiley‐VCH.…”

FerriIridium: A Lysosome‐Targeting Iron(III)‐Activated Iridium(III) Prodrug for Chemotherapy in Gastric Cancer Cells

“…The group of Rodriguez reported salinomycin‐based drugs that can sequester iron in lysosomes to kill cancer stem cells . The group of Mokhir also reported lysosome‐targeting, ROS‐producing prodrugs . The aforementioned studies focus on only one aspect, either iron‐activated probes or iron‐targeting therapy.…”