Molecules
Molecules
5 years ago

Carbamates as Potential Prodrugs and a New Warhead for HDAC Inhibition.

Jelena Melesina, Manfred Jung, Wolfgang Sippl, Kristina King, Alexander-Thomas Hauser
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.

Publisher URL: http://doi.org/10.3390/molecules23020321

DOI: 10.3390/molecules23020321

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