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Azologization and repurposing of a hetero-stilbene-based kinase inhibitor: towards the design of photoswitchable sirtuin inhibitors

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. A hetero-stilbene lead resulting from the screening of a compound that was originally designed as kinase inhibitor...

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Autores principales: Grathwol, Christoph W, Wössner, Nathalie, Swyter, Sören, Smith, Adam C, Tapavicza, Enrico, Hofstetter, Robert K, Bodtke, Anja, Jung, Manfred, Link, Andreas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Beilstein-Institut 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774072/
https://www.ncbi.nlm.nih.gov/pubmed/31598174
http://dx.doi.org/10.3762/bjoc.15.214
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author Grathwol, Christoph W
Wössner, Nathalie
Swyter, Sören
Smith, Adam C
Tapavicza, Enrico
Hofstetter, Robert K
Bodtke, Anja
Jung, Manfred
Link, Andreas
author_facet Grathwol, Christoph W
Wössner, Nathalie
Swyter, Sören
Smith, Adam C
Tapavicza, Enrico
Hofstetter, Robert K
Bodtke, Anja
Jung, Manfred
Link, Andreas
author_sort Grathwol, Christoph W
collection PubMed
description 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. A hetero-stilbene lead resulting from the screening of a compound that was originally designed as kinase inhibitor served as a starting point for the design of photoswitchable sirtuin inhibitors. Because the original stilbenoid structure exerted unfavourable photochemical characteristics it was remodelled to its heteroarylic diazeno analogue. By this intramolecular 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 long-lived (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.
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spelling pubmed-67740722019-10-09 Azologization and repurposing of a hetero-stilbene-based kinase inhibitor: towards the design of photoswitchable sirtuin inhibitors Grathwol, Christoph W Wössner, Nathalie Swyter, Sören Smith, Adam C Tapavicza, Enrico Hofstetter, Robert K Bodtke, Anja Jung, Manfred Link, Andreas Beilstein J Org Chem Full Research Paper 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. A hetero-stilbene lead resulting from the screening of a compound that was originally designed as kinase inhibitor served as a starting point for the design of photoswitchable sirtuin inhibitors. Because the original stilbenoid structure exerted unfavourable photochemical characteristics it was remodelled to its heteroarylic diazeno analogue. By this intramolecular 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 long-lived (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. Beilstein-Institut 2019-09-16 /pmc/articles/PMC6774072/ /pubmed/31598174 http://dx.doi.org/10.3762/bjoc.15.214 Text en Copyright © 2019, Grathwol et al. https://creativecommons.org/licenses/by/4.0https://www.beilstein-journals.org/bjoc/termsThis is an Open Access article under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0). Please note that the reuse, redistribution and reproduction in particular requires that the authors and source are credited. The license is subject to the Beilstein Journal of Organic Chemistry terms and conditions: (https://www.beilstein-journals.org/bjoc/terms)
spellingShingle Full Research Paper
Grathwol, Christoph W
Wössner, Nathalie
Swyter, Sören
Smith, Adam C
Tapavicza, Enrico
Hofstetter, Robert K
Bodtke, Anja
Jung, Manfred
Link, Andreas
Azologization and repurposing of a hetero-stilbene-based kinase inhibitor: towards the design of photoswitchable sirtuin inhibitors
title Azologization and repurposing of a hetero-stilbene-based kinase inhibitor: towards the design of photoswitchable sirtuin inhibitors
title_full Azologization and repurposing of a hetero-stilbene-based kinase inhibitor: towards the design of photoswitchable sirtuin inhibitors
title_fullStr Azologization and repurposing of a hetero-stilbene-based kinase inhibitor: towards the design of photoswitchable sirtuin inhibitors
title_full_unstemmed Azologization and repurposing of a hetero-stilbene-based kinase inhibitor: towards the design of photoswitchable sirtuin inhibitors
title_short Azologization and repurposing of a hetero-stilbene-based kinase inhibitor: towards the design of photoswitchable sirtuin inhibitors
title_sort azologization and repurposing of a hetero-stilbene-based kinase inhibitor: towards the design of photoswitchable sirtuin inhibitors
topic Full Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774072/
https://www.ncbi.nlm.nih.gov/pubmed/31598174
http://dx.doi.org/10.3762/bjoc.15.214
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