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Lysosome-Targeting Amplifiers of Reactive Oxygen Species as Anticancer Prodrugs.
Lysosome-Targeting Amplifiers of Reactive Oxygen Species as Anticancer Prodrugs.
- 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.)
- Subjects :
- Animals
Antineoplastic Agents chemistry
Cell Line
Cell Proliferation drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Lysosomes metabolism
Mice
Neoplasms metabolism
Neoplasms pathology
Neoplasms, Experimental drug therapy
Neoplasms, Experimental metabolism
Neoplasms, Experimental pathology
Prodrugs chemistry
Reactive Oxygen Species metabolism
Structure-Activity Relationship
Antineoplastic Agents pharmacology
Lysosomes drug effects
Neoplasms drug therapy
Prodrugs pharmacology
Reactive Oxygen Species antagonists & inhibitors
Subjects
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