Activation of Sirtuin 2 Inhibitors Employing Photoswitchable Geometry and Aqueous Solubility.
azo dyes
epigenetics
photopharmacology
photoswitches
sirtuins
Journal
ChemMedChem
ISSN: 1860-7187
Titre abrégé: ChemMedChem
Pays: Germany
ID NLM: 101259013
Informations de publication
Date de publication:
05 08 2020
05 08 2020
Historique:
received:
06
03
2020
revised:
20
04
2020
pubmed:
22
4
2020
medline:
16
6
2021
entrez:
22
4
2020
Statut:
ppublish
Résumé
Because isoenzymes of the experimentally and therapeutically extremely relevant sirtuin family show high similarity, addressing the unique selectivity pocket of sirtuin 2 is a promising strategy towards selective inhibitors. An unrelated approach towards selective inhibition of isoenzymes with varied tissue distribution is targeted drug delivery or spatiotemporal activation by photochemical activation. Azologization of two nicotinamide-mimicking lead structures was undertaken to combine both approaches and yielded a set of 33 azobenzenes and azopyridines that have been evaluated for their photochemical behaviour and bioactivity. For some compounds, inhibitory activity reached the sub-micromolar range in their thermodynamically favoured E form and could be decreased by photoisomerization to the metastable Z form. Besides, derivatization with long-chain fatty acids yielded potent sirtuin 2 inhibitors, featuring another intriguing aspect of azo-based photoswitches. In these compounds, switching to the Z isomer increased aqueous solubility and thereby enhanced biological activity by up to a factor of 21. The biological activity of two compounds was confirmed by hyperacetylation of sirtuin specific histone proteins in a cell-based activity assay.
Identifiants
pubmed: 32314517
doi: 10.1002/cmdc.202000148
pmc: PMC7496931
doi:
Substances chimiques
Azo Compounds
0
Enzyme Inhibitors
0
Pyridines
0
Water
059QF0KO0R
SIRT2 protein, human
EC 3.5.1.-
Sirtuin 2
EC 3.5.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1480-1489Informations de copyright
© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
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