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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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Beilstein-Institut
2019
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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. |
format | Online Article Text |
id | pubmed-6774072 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Beilstein-Institut |
record_format | MEDLINE/PubMed |
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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