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Lysosome‐Targeting Amplifiers of Reactive Oxygen Species as Anticancer Prodrugs
Author(s) -
Daum Steffen,
Reshetnikov M. S. Viktor,
Sisa Miroslav,
Dumych Tetyana,
Lootsik Maxim D.,
Bilyy Rostyslav,
Bila Evgenia,
Janko Christina,
Alexiou Christoph,
Herrmann Martin,
Sellner Leopold,
Mokhir Andriy
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201706585
Subject(s) - prodrug , lysosome , phenylboronic acid , pinacol , reactive oxygen species , chemistry , cancer cell , cytotoxicity , in vitro , biochemistry , cancer , biology , catalysis , enzyme , genetics
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 (IC 50 =3.5–7.2 μ m ) and in vivo (40 mg kg −1 , NK/Ly murine model) but remained weakly toxic towards non‐malignant cells (IC 50 =15–30 μ m ).