† Institute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg, Albertstraße 25, 79104 Freiburg, Germany
‡ Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, Wolfgang-Langenbeck-Straße 4, 06120 Halle (Saale), Germany
§ Département de Biologie Structurale Intégrative, Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UDS), CNRS, INSERM, 1 Rue Laurent Fries, 67404 Illkirch Cedex, France
∥ Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Centre (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
This article is part of the Epigenetics special issue.
Abstract
Histone deacetylase 6 (HDAC6) catalyzes the removal of an acetyl group from lysine residues of several non-histone proteins. Here we report the preparation of thiazole-, oxazole-, and oxadiazole-containing biarylhydroxamic acids by a short synthetic procedure. We identified them as selective HDAC6 inhibitors by investigating the inhibition of recombinant HDAC enzymes and the protein acetylation in cells by Western blotting (tubulin vs histone acetylation). The most active compounds exhibited nanomolar potency and high selectivity for HDAC6. For example, an oxazole hydroxamate inhibits HDAC6 with an IC50 of 59 nM and has a selectivity index of >200 against HDAC1 and HDAC8. This is the first report showing that the nature of a heterocycle directly connected to a zinc binding group (ZBG) can be used to modulate subtype selectivity and potency for HDAC6 inhibitors to such an extent. We rationalize the high potency and selectivity of the oxazoles by molecular modeling and docking.
Citation data is made available by participants in CrossRef's Cited-by Linking service. For a more comprehensive list of citations to this article, users are encouraged to perform a search in SciFinder.
Abstract: Novel selective histone deacetylase 6 (HDAC6) inhibitors using the quinazoline as the cap were designed, synthesized, and evaluated for HDAC enzymatic assays. N-Hydroxy-4-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)butanamide, 23bb, was the ...
Rodrigues, Ferreira-Silva, Ferreira, Fernandes, Kwee, Sant’Anna, Ionta, and Fraga
201659 (2), pp 655–670
Abstract: This manuscript describes a novel class of N-acylhydrazone (NAH) derivatives that act as histone deacetylase (HDAC) 6/8 dual inhibitors and were designed from the structure of trichostatin A (1). Para-substituted phenyl-hydroxamic acids presented a more ...
Abstract: Schistosomiasis is a major neglected parasitic disease that affects more than 265 million people worldwide and for which the control strategy consists of mass treatment with the only available drug, praziquantel. In this study, a series of new ...
Rabal, Sánchez-Arias, Cuadrado-Tejedor, de Miguel, Pérez-González, García-Barroso, Ugarte, Estella-Hermoso de Mendoza, Sáez, Espelosin, Ursua, Haizhong, Wei, Musheng, Garcia-Osta, and Oyarzabal
201659 (19), pp 8967–9004
Abstract: Simultaneous inhibition of phosphodiesterase 5 (PDE5) and histone deacetylases (HDAC) has recently been validated as a potentially novel therapeutic approach for Alzheimer’s disease (AD). To further extend this concept, we designed and synthesized the ...
Yang, Mustafa, Tan, Poulsen, Ramanujulu, Chng, Yen, and Dymock
201659 (18), pp 8233–8262
Abstract: Blockage of more than one oncoprotein or pathway is now a standard approach in modern cancer therapy. Multiple inhibition is typically achieved with two or more drugs. Herein, we describe a pharmacophore merging strategy combining the JAK2/FLT3 inhibitor ...
Abstract: Histone deacetylase 6 (HDAC6) removes the acetyl group from lysine residues in a number of non-histone substrates and plays important roles in microtubule dynamics and chaperone activities. There is growing interest in identifying HDAC6-selective ...
Learn more about these metrics Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.
The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.
Synthesis and Biological Investigation of Oxazole Hydroxamates as Highly Selective Histone Deacetylase 6 (HDAC6) Inhibitors
J. Med. Chem., 2016, 59 (4), pp 1545–1555
This article is part of the Epigenetics special issue.
Abstract
Histone deacetylase 6 (HDAC6) catalyzes the removal of an acetyl group from lysine residues of several non-histone proteins.
Here we report the preparation of thiazole-, oxazole-, and oxadiazole-containing biarylhydroxamic acids by a short synthetic procedure.
We identified them as selective HDAC6 inhibitors by investigating the inhibition of recombinant HDAC enzymes and the protein acetylation in cells by Western blotting (tubulin vs histone acetylation).
The most active compounds exhibited nanomolar potency and high selectivity for HDAC6. For example, an oxazole hydroxamate inhibits HDAC6 with an IC50 of 59 nM and has a selectivity index of >200 against HDAC1 and HDAC8.
This is the first report showing that the nature of a heterocycle directly connected to a zinc binding group (ZBG) can be used to modulate subtype selectivity and potency for HDAC6 inhibitors to such an extent. We rationalize the high potency and selectivity of the oxazoles by molecular modeling and docking.
This review showcases various coupling reagents which have been implemented specifically for large-scale amide synthesis via the condensation of an acid and amine, while highlighting the benefits and drawbacks of each reagent on an industrial scale.
Citation data is made available by participants in CrossRef's Cited-by Linking service. For a more comprehensive list of citations to this article, users are encouraged to perform a search in SciFinder.
AndreyTolmachev, Andrey V.Bogolubsky, Sergey E.Pipko, Alexander V.Grishchenko, Dmytro V.Ushakov, Anton V.Zhemera, Oleksandr O.Viniychuk, Anzhelika I.Konovets, Olga A.Zaporozhets, Pavel K.Mykhailiuk, and Yurii S.Moroz
Babij, McCusker, Whiteker, Canturk, Choy, Creemer, Amicis, Hewlett, Johnson, Knobelsdorf, Li, Lorsbach, Nugent, Ryan, Smith, and Yang
201620 (3), pp 661–667
Abstract: The 1H and 13C NMR chemical shifts of 48 industrially preferred solvents in six commonly used deuterated NMR solvents (CDCl3, acetone-d6, DMSO-d6, acetonitrile-d3, methanol-d4, and D2O) are reported. This work supplements the compilation of NMR data ...
Abstract: The development of a concise asymmetric synthesis of the antiviral development candidate letermovir is reported, proceeding in >60% yield over a total of seven steps from commercially available materials. Key to the effectiveness of this process is a ...
Abstract: An expedient, practical, and enantioselective route to the highly congested ent-kaurane diterpene maoecrystal V is presented. This route, which has been several years in the making, is loosely modeled after a key pinacol shift in the proposed ...
