Lysosome-Targeting Amplifiers of Reactive Oxygen Species as Anticancer Prodrugs
| Autor: | Christina Janko, Maxim D. Lootsik, Tetyana Dumych, Christoph Alexiou, Andriy Mokhir, Leopold Sellner, Rostyslav Bilyy, Miroslav Sisa, Martin Herrmann, Evgenia Bila, Steffen Daum, M. S. Viktor Reshetnikov |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Antineoplastic Agents 010402 general chemistry 01 natural sciences Catalysis Cell Line chemistry.chemical_compound Mice Structure-Activity Relationship 03 medical and health sciences In vivo Lysosome Neoplasms medicine Animals Humans Prodrugs Phenylboronic acid IC50 Cell Proliferation chemistry.chemical_classification Reactive oxygen species Dose-Response Relationship Drug Chemistry Pinacol 010405 organic chemistry General Chemistry Neoplasms Experimental General Medicine Prodrug 0104 chemical sciences medicine.anatomical_structure 030104 developmental biology Biochemistry Cancer cell Drug Screening Assays Antitumor Lysosomes Reactive Oxygen Species |
| Zdroj: | Angewandte Chemie. 129:15751-15755 |
| ISSN: | 0044-8249 |
| DOI: | 10.1002/ange.201706585 |
| Popis: | 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). |
| Databáze: | OpenAIRE |
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