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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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Publication details

The article was received on 08 May 2014, accepted on 06 Aug 2014 and first published on 11 Aug 2014


Article type: Edge Article
DOI: 10.1039/C4SC01346H
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Citation: Chem. Sci., 2014,5, 4794-4799
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    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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