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Open AccessFeature PaperArticle

Carbamates as Potential Prodrugs and a New Warhead for HDAC Inhibition

Institute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg, Albertstraße 25, 79104 Freiburg im Breisgau, Germany
Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, Wolfgang-Langenbeck-Straße 4, 06120 Halle (Saale), Germany
Author to whom correspondence should be addressed.
Molecules 2018, 23(2), 321;
Received: 10 January 2018 / Revised: 25 January 2018 / Accepted: 31 January 2018 / Published: 2 February 2018
(This article belongs to the Special Issue Modulators of Histone Acetylation: A Medicinal Chemistry Perspective)
We designed and synthesized carbamates of the clinically-approved HDAC (histone deacetylase) inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) in order to validate our previously-proposed hypothesis that these carbamates might serve as prodrugs for hydroxamic acid containing HDAC inhibitors. Biochemical assays proved our new compounds to be potent inhibitors of histone deacetylases in vitro, and they also showed antiproliferative effects in leukemic cells. These results, as well as stability analysis led to the suggestion that the intact carbamates are inhibitors of histone deacetylases themselves, representing a new zinc-binding warhead in HDAC inhibitor design. This suggestion was further supported by the synthesis and evaluation of a carbamate derivative of the HDAC6-selective inhibitor bufexamac. View Full-Text
Keywords: epigenetics; histone deacetylases; HDACs; hydroxamic acids; prodrug concept epigenetics; histone deacetylases; HDACs; hydroxamic acids; prodrug concept
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MDPI and ACS Style

King, K.; Hauser, A.-T.; Melesina, J.; Sippl, W.; Jung, M. Carbamates as Potential Prodrugs and a New Warhead for HDAC Inhibition. Molecules 2018, 23, 321.

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