- Aminothiazoles as Potent and Selective Sirt2 Inhibitors: A Structure-Activity Relationship Study
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Sirtuins are NAD+-dependent protein deacylases that cleave off acetyl but also other acyl groups from the ε-amino group of lysines in histones and other substrate proteins. Dysregulation of human Sirt2 (hSirt2) activity has been associated with the pathogenesis of cancer, inflammation, and neurodegeneration, which makes the modulation of hSirt2 activity a promising strategy for pharmaceutical intervention. The sirtuin rearranging ligands (SirReals) have recently been discovered by us as highly potent and isotype-selective hSirt2 inhibitors. Here, we present a well-defined structure-activity relationship study, which rationalizes the unique features of the SirReals and probes the limits of modifications on this scaffold regarding inhibitor potency. Moreover, we present a crystal structure of hSirt2 in complex with an optimized SirReal derivative that exhibits an improved in vitro activity. Lastly, we show cellular hyperacetylation of the hSirt2 targeted tubulin caused by our improved lead structure.
- Schiedel, Matthias,Rumpf, Tobias,Karaman, Berin,Lehotzky, Attila,Oláh, Judit,Gerhardt, Stefan,Ovádi, Judit,Sippl, Wolfgang,Einsle, Oliver,Jung, Manfred
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supporting information
p. 1599 - 1612
(2016/03/05)
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- Nitrogen-containing heterocycles from metal β-diketonates
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Factors determining the reaction of metal β-diketonates with hydrazine, in particular the nature of central metal ion and structure of β-diketonate ligand, are discussed. The possibility for the preparation of other heterocyclic compounds via reaction of metal acetylacetonates with phenylhydrazine, o-phenylenediamine, urea, and thiourea was studied.
- Svistunova,Shapkin,Nikolaeva,Apanasenko
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experimental part
p. 756 - 761
(2011/08/06)
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- CYCLIZATION KINETICS AND MECHANISM OF N-BENZOYL-N'-(1,2-DIMETHYL-3-OXO-1-BUTENYL)THIOUREA
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Cyclization kinetics of N-benzoyl-N'-(1,2-dimethyl-3-oxo-1-butenyl)thiourea have been studied in aqueous and methanolic solutions of acids and bases.In all cases the cyclization product is 4,5,6-trimethyl-2,5-dihydro-2-thioxopyrimidine or its protonated or deprotonated forms.In dilute methanolic and aqueous hydrochloric acid the substrate reacts in its monoprotonated form.The cyclization in basic media is catalyzed by methoxide or hydroxyl ion and also by primary and secondary amines at such pH values were the catalysis by lyate ion is practically insignificant.Tertiary amines and acetate ion do not catalyze the cyclization.
- Kavalek, Jaromir,Potesil, Tomas,Sterba, Vojeslav
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p. 578 - 585
(2007/10/02)
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