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).

Danylo Halytsky Lviv National Medical University Pekarska str 69 79010 Lviv Ukraine

Department of Internal Medicine 3 Rheumatology and Immunology University Hospital Erlangen Friedrich Alexander Universität Erlangen Nürnberg 91054 Erlangen Germany

Department of Medicine 5 University Hospital Heidelberg Im Neuenheimer Feld 410 69120 Heidelberg Germany

Department of Organic Chemistry Ivan Franko Lviv National University Kyrylo and Mefodiy Str 6 79005 Lviv Ukraine

Department of Otorhinolaryngology Head and Neck Surgery Section of Experimental Oncology and Nanomedicine University Hospital Erlangen Glückstraße 10a 91054 Erlangen Germany

Friedrich Alexander University of Erlangen Nürnberg Department of Chemistry and Pharmacy Organic Chemistry Chair 2 Henkestr 42 91054 Erlangen Germany

Institute of Experimental Botany AS CR Prague Czech Republik

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