Azologization of a hetero-stilbene based c-RAF kinase inhibitor: Towards the design of photoswitchable sirtuin inhibitors

Submitting author affiliation:
Universität Greifswald, Greifswald, Germany

Beilstein Arch. 2019, 201953.

Published 01 Jul 2019

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The use of light as an external trigger to change ligand shape and as a result its bioactivity, allows the probing of pharmacologically relevant systems with spatiotemporal resolution. In this context, aromatic diazeno compounds are well suited for the design of photoswitchable ligands due to the long thermal relaxation half‐lives of the photoinduced Z configuration, and tunability of the absorption wavelength λmax. In search for sirtuin inhibitors, a hetero-stilbene lead resulting from the screening of a compound that was originally designed as kinase inhibitor, was remodelled to its diazeno analogue. By this azologization, the shape of the molecule was left unaltered whereas the photoswitching ability was improved. As anticipated, the highly analogous compound showed similar activity in its thermodynamically stable stretched-out E form. Irradiation of this isomer triggers isomerisation to the Z configuration with a bent geometry causing a considerably shorter end‐to‐end distance. The resulting affinity shifts are intended to enable real‐time photomodulation of sirtuins in vitro.

Keywords: azo compounds; epigenetics; photoswitch; sirtuins; stilbenes

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Grathwol, C. W.; Wössner, N.; Swyter, S.; Smith, A. C.; Tapavicza, E.; Hofstetter, R. K.; Bodtke, A.; Jung, M.; Link, A. Beilstein Arch. 2019, 201953. doi:10.3762/bxiv.2019.53.v1

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