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Issue 12, 2014
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Chromo-pharmacophores: photochromic diarylmaleimide inhibitors for sirtuins

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Abstract

Controlling the activity of sirtuins is of high biomedical relevance as the enzymes are involved in cancer, neurodegeneration and other diseases. Therefore structural elements of 3,4-bisindoylmaleimides (BIMs), which are known NAD+-dependent histone deacetylase (sirtuin) inhibitors, were merged with photochromic diarylmaleimides to yield photoswitchable enzyme inhibitors. The new inhibitors show excellent photophysical properties, are switchable even in polar solvents, and subtype selective against hSirt2. The inhibitory activity changes up to a factor of 22 for the two photoisomers and physiological properties can therefore be effectively toggled by irradiation with light of different wavelengths. Docking experiments using the enzyme crystal structure explain the observed activity changes based on the steric demand of the thiophene substitution and the rigidity of the molecular structure.

Graphical abstract: Chromo-pharmacophores: photochromic diarylmaleimide inhibitors for sirtuins

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Supplementary files

Article information


Submitted
08 May 2014
Accepted
06 Aug 2014
First published
11 Aug 2014

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2014,5, 4794-4799
Article type
Edge Article
Author version available

Chromo-pharmacophores: photochromic diarylmaleimide inhibitors for sirtuins

C. Falenczyk, M. Schiedel, B. Karaman, T. Rumpf, N. Kuzmanovic, M. Grøtli, W. Sippl, M. Jung and B. König, Chem. Sci., 2014, 5, 4794
DOI: 10.1039/C4SC01346H

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