Abstract
Bioorthogonal uncaging strategies have recently emerged as an experimental therapeutic approach to control drug release. Herein we report a novel masking strategy that enables to modulate the metal chelating properties of hydroxamic acid groups by bioorthogonal chemistry using Pd-functionalized resins. This novel approach allowed to devise an inactive precursor of the histone deacetylase inhibitor vorinostat that was efficiently uncaged by heterogeneous Pd catalysis in cell culture models of glioma and lung cancer.
Highlights
The activation of prodrugs by benign chemical processes that are not reliant on intrinsic biological mediators have the potential to achieve a superior control over the area where drugs are generated, minimizing untoward drug release and consequent adverse effects
The feasibility of such an approach has been recently demonstrated in cancer cell culture with two different strategies: metal-free click-to-release chemistry[1−3] and transition metal-mediated bioorthogonal deprotection chemistry.[4−8] The latter strategy provides a nonenzymatic method to trigger multiple druguncaging cycles per catalyst molecule
Encouraged by this, our lab is exploring new chemistries to develop novel caged chemotherapeutic agents that are released by bioorthogonal means, via heterogeneous Pd catalysis.[4−7] To design an efficient bioorthogonal prodrug, it is fundamental to identify and mask the drug’s functional group that is most essential for its cytotoxic mode of action
Summary
The activation of prodrugs by benign chemical processes that are not reliant on intrinsic biological mediators have the potential to achieve a superior control over the area where drugs are generated (e.g., tissues, organs, cells), minimizing untoward drug release and consequent adverse effects. One of the distinctive opportunities offered by the application of bioorthogonal activation methods in cancer therapy is that it could be exploited to uncage multiple designed chemotherapy precursors using the same triggering stimulus, enabling the controlled release, concurrent or successively, of synergistic therapeutics at the same anatomical area (e.g., inside a tumor where a Pdfunctionalized device has been inserted) Such an approach may offer a safer way to treat locally advanced cancers through drug combinations and, potentially, overcome chemoresistance.
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