Imatinib is the first protein kinase inhibitor approved for clinical use and is a seminal drug for the concept of targeted therapy. Herein we report on the design, synthesis, photokinetic properties, and in vitro enzymatic evaluation of a photoactivatable caged prodrug of imatinib. This approach allows spatial and temporal control over the activation of imatinib triggered by ultraviolet light. The successful application of the photoactivation concept to this significant kinase inhibitor provides further evidence for the caging technique as a feasible approach in the kinase field. The presented photoactivatable imatinib prodrug will be highly useful as a pharmacological tool to study the impact of imatinib toward biological systems in greater detail.

Photoremovable protecting groups added to bioactive molecules provide spatial and temporal control of the biological effects. We present synthesis and characterization of the first photoactivatable small-molecule tubulin inhibitor. By blocking the pharmacophoric OH group on compound with photoremovable 4,5-dimethoxy-2-nitrobenzyl moiety we developed the photocaged prodrug that had no effect in biological assays. Short UV light exposure of the derivative or UV-irradiation of cells treated with resulted in fast and potent inhibition of tubulin polymerization, attenuation of cell viability, and apoptotic cell death, implicating release of the parent active compound. This study validates for the first time the photoactivatable prodrug concept in the field of small molecule tubulin inhibitors. The caged derivative represents a novel tool in antitubulin approaches.

Abstract:In this study, we report on the design, synthesis, photokinetic properties and in vitro evaluation of photoactivatable caged prodrugs for the receptor tyrosine kinase VEGFR-2. Highly potent VEGFR-2 inhibitors 1 and 3 were caged by introduction of a photoremovable protecting group (PPG) to yield the caged prodrugs 4 and 5. As expected, enzymatic and cellular proliferation assays showed dramatically diminished efficacy of caged prodrugs in vitro. Upon ultraviolet (UV) irradiation of the prodrugs original inhibitory activity was completely restored and even distinctly reinforced, as was the case for the prodrug 4. The presented results are a further evidence for caging technique being an interesting approach in the protein kinase field. It could enable spatial and temporal control for the inhibition of VEGFR-2. The described photoactivatable prodrugs might be highly useful as biological probes for studying the VEGFR-2 signal transduction.

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