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Article

Photoswitchable Azo- and Diazocine-Functionalized Derivatives of the VEGFR-2 Inhibitor Axitinib

1
Institute of Pharmacy, Christian-Albrechts-University of Kiel, 24118 Kiel, Germany
2
Otto-Diels-Institute of Organic Chemistry, Christian-Albrechts-University of Kiel, 24098 Kiel, Germany
3
Laboratory of Radiobiology & Experimental Radiooncology and UCCH Kinomics Core Facility, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(23), 8961; https://doi.org/10.3390/ijms21238961
Received: 28 September 2020 / Revised: 21 November 2020 / Accepted: 22 November 2020 / Published: 25 November 2020
(This article belongs to the Special Issue Protein Kinases: Function, Substrates, and Implication in Diseases)
In this study, we aimed at the application of the concept of photopharmacology to the approved vascular endothelial growth factor receptor (VEGFR)-2 kinase inhibitor axitinib. In a previous study, we found out that the photoisomerization of axitinib’s stilbene-like double bond is unidirectional in aqueous solution due to a competing irreversible [2+2]-cycloaddition. Therefore, we next set out to azologize axitinib by means of incorporating azobenzenes as well as diazocine moieties as photoresponsive elements. Conceptually, diazocines (bridged azobenzenes) show favorable photoswitching properties compared to standard azobenzenes because the thermodynamically stable Z-isomer usually is bioinactive, and back isomerization from the bioactive E-isomer occurs thermally. Here, we report on the development of different sulfur–diazocines and carbon–diazocines attached to the axitinib pharmacophore that allow switching the VEGFR-2 activity reversibly. For the best sulfur–diazocine, we could verify in a VEGFR-2 kinase assay that the Z-isomer is biologically inactive (IC50 >> 10,000 nM), while significant VEGFR-2 inhibition can be observed after irradiation with blue light (405 nm), resulting in an IC50 value of 214 nM. In summary, we could successfully develop reversibly photoswitchable kinase inhibitors that exhibit more than 40-fold differences in biological activities upon irradiation. Moreover, we demonstrate the potential advantage of diazocine photoswitches over standard azobenzenes. View Full-Text
Keywords: photopharmacology; diazocine; azobenzene; photoswitchable kinase inhibitor; axitinib; VEGFR photopharmacology; diazocine; azobenzene; photoswitchable kinase inhibitor; axitinib; VEGFR
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MDPI and ACS Style

Heintze, L.; Schmidt, D.; Rodat, T.; Witt, L.; Ewert, J.; Kriegs, M.; Herges, R.; Peifer, C. Photoswitchable Azo- and Diazocine-Functionalized Derivatives of the VEGFR-2 Inhibitor Axitinib. Int. J. Mol. Sci. 2020, 21, 8961. https://doi.org/10.3390/ijms21238961

AMA Style

Heintze L, Schmidt D, Rodat T, Witt L, Ewert J, Kriegs M, Herges R, Peifer C. Photoswitchable Azo- and Diazocine-Functionalized Derivatives of the VEGFR-2 Inhibitor Axitinib. International Journal of Molecular Sciences. 2020; 21(23):8961. https://doi.org/10.3390/ijms21238961

Chicago/Turabian Style

Heintze, Linda, Dorian Schmidt, Theo Rodat, Lydia Witt, Julia Ewert, Malte Kriegs, Rainer Herges, and Christian Peifer. 2020. "Photoswitchable Azo- and Diazocine-Functionalized Derivatives of the VEGFR-2 Inhibitor Axitinib" International Journal of Molecular Sciences 21, no. 23: 8961. https://doi.org/10.3390/ijms21238961

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