Schehr, Miriam, Ianes, Chiara, Weisner, Joern, Heintze, Linda, Mueller, Matthias P., Pichlo, Christian, Charl, Julia, Brunstein, Elena, Ewert, Julia, Lehr, Marc, Baumann, Ulrich, Rauh, Daniel, Knippschild, Uwe, Peifer, Christian and Herges, Rainer (2019). 2-Azo-, 2-diazocine-thiazols and 2-azo-imidazoles as photoswitchable kinase inhibitors: limitations and pitfalls of the photoswitchable inhibitor approach. Photochem. Photobiol. Sci., 18 (6). S. 1398 - 1408. CAMBRIDGE: ROYAL SOC CHEMISTRY. ISSN 1474-9092

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Abstract

In photopharmacology, photoswitchable compounds including azobenzene or other diarylazo moieties exhibit bioactivity against a target protein typically in the slender E-configuration, whereas the rather bulky Z-configuration usually is pharmacologically less potent. Herein we report the design, synthesis and photochemical/inhibitory characterization of new photoswitchable kinase inhibitors targeting p38a MAPK and CK1d. A well characterized inhibitor scaffold was used to attach arylazo-and diazocine moieties. When the isolated isomers, or the photostationary state (PSS) of isomers, were tested in commonly used in vitro kinase assays, however, only small differences in activity were observed. X-ray analyses of ligandbound p38a MAPK and CK1d complexes revealed dynamic conformational adaptations of the protein with respect to both isomers. More importantly, irreversible reduction of the azo group to the corresponding hydrazine was observed. Independent experiments revealed that reducing agents such as DTT (dithiothreitol) and GSH (glutathione) that are typically used for protein stabilization in biological assays were responsible. Two further sources of error are the concentration dependence of the E-Z-switching efficiency and artefacts due to incomplete exclusion of light during testing. Our findings may also apply to a number of previously investigated azobenzene-based photoswitchable inhibitors.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Schehr, MiriamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ianes, ChiaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weisner, JoernUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heintze, LindaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, Matthias P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pichlo, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Charl, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brunstein, ElenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ewert, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lehr, MarcUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baumann, UlrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rauh, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Knippschild, UweUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peifer, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herges, RainerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-146568
DOI: 10.1039/c9pp00010k
Journal or Publication Title: Photochem. Photobiol. Sci.
Volume: 18
Number: 6
Page Range: S. 1398 - 1408
Date: 2019
Publisher: ROYAL SOC CHEMISTRY
Place of Publication: CAMBRIDGE
ISSN: 1474-9092
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
TARGETING CANCER; AZOBENZENE; ISOMERIZATION; IMIDAZOLES; TRANSMultiple languages
Biochemistry & Molecular Biology; Biophysics; Chemistry, PhysicalMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/14656

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