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Lysosome-Targeting Amplifiers of Reactive Oxygen Species as Anticancer Prodrugs.

Lysosome-Targeting Amplifiers of Reactive Oxygen Species as Anticancer Prodrugs.

Authors :
Daum S
Reshetnikov MSV
Sisa M
Dumych T
Lootsik MD
Bilyy R
Bila E
Janko C
Alexiou C
Herrmann M
Sellner L
Mokhir A
Source :
Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2017 Dec 04; Vol. 56 (49), pp. 15545-15549. Date of Electronic Publication: 2017 Nov 09.
Publication Year :
2017

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 (IC <subscript>50</subscript> =3.5-7.2 μm) and in vivo (40 mg kg <superscript>-1</superscript> , NK/Ly murine model) but remained weakly toxic towards non-malignant cells (IC <subscript>50</subscript> =15-30 μm).<br /> (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Details

Language :
English
ISSN :
1521-3773
Volume :
56
Issue :
49
Database :
MEDLINE
Journal :
Angewandte Chemie (International ed. in English)
Publication Type :
Academic Journal
Accession number :
28994179
Full Text :
https://doi.org/10.1002/anie.201706585