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Lysosome-Targeting Amplifiers of Reactive Oxygen Species as Anticancer Prodrugs

Lysosome-Targeting Amplifiers of Reactive Oxygen Species as Anticancer Prodrugs

Steffen Daum, M S Viktor Reshetnikov, Miroslav Sisa, Tetyana Dumych, Maxim D Lootsik, Rostyslav Bilyy, Evgenia Bila, Christina Janko, Christoph Alexiou, Martin Herrmann, Leopold Sellner, Andriy Mokhir

Angew Chem Int Ed Engl. 2017 Dec 4;56(49):15545-15549.

PMID: 28994179

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 (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).

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
LS793399	4-(N-cyclopropylsulfonamide)phenylboronic acid pinacol ester			Price
LS793437	3-(Tetrahydrofurfurylaminocarbonyl)phenylboronic acid pinacol ester			Price

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