Carbamates as Potential Prodrugs and a New Warhead for HDAC Inhibition

Molecules

Manfred Jung¹  Alexander-Thomas Hauser¹  Kristina King¹  Jelena Melesina²  Wolfgang Sippl² 

[1] 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;

关键词: epigenetics;    histone deacetylases;    HDACs;    hydroxamic acids;    prodrug concept;   

DOI  :  10.3390/molecules23020321

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown