Lysosome-Targeting Amplifiers of Reactive Oxygen Species as Anticancer Prodrugs

0485730 - ÚEB 2018 RIV DE eng J - Článek v odborném periodiku
Daum, S. - Reshetnikov, M.S.V. - Šíša, Miroslav - Dumych, T. - Lootsik, M. D. - Bilyy, R. - Bila, E. - Janko, C. - Alexiou, C. - Herrmann, M. - Sellner, L. - Mokhir, A.
Lysosome-Targeting Amplifiers of Reactive Oxygen Species as Anticancer Prodrugs.
Angewandte Chemie - International Edition. Roč. 56, č. 49 (2017), s. 15545-15549. ISSN 1433-7851. E-ISSN 1521-3773
Institucionální podpora: RVO:61389030
Klíčová slova: aminoferrocene * cancer * lysosomes * prodrugs * reactive oxygen species
Obor OECD: Organic chemistry
Impakt faktor: 12.102, rok: 2017

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 μm) and in vivo (40 mg kg −1 , NK/Ly murine model) but remained weakly toxic towards non-malignant cells (IC 50 =15–30 μm).
Trvalý link: http://hdl.handle.net/11104/0280677