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Natural and Synthetic Macrocyclic Inhibitors of the Histone Deacetylase Enzymes
Author(s) -
Maola Alex R.,
Kristensen Helle M. E.,
Leman Luke J.,
Ghadiri M. Reza,
Olsen Christian A.
Publication year - 2017
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201600519
Subject(s) - histone deacetylase , hydroxamic acid , isozyme , enzyme , chemistry , biochemistry , drug discovery , small molecule , drug , combinatorial chemistry , histone , computational biology , pharmacology , biology , stereochemistry , gene
Inhibition of histone deacetylase (HDAC) enzymes has emerged as a target for development of cancer chemotherapy. Four compounds have gained approval for clinical use by the Food and Drug Administration in the US, and several are currently in clinical trials. However, none of these compounds possesses particularly good isozyme selectivity, which would be a highly desirable feature in a tool compound. Whether selective inhibition of individual HDAC isozymes will provide improved drug candidates remains to be seen. Nevertheless, it has been speculated that using macrocyclic compounds to target HDAC enzymes might hold an advantage over the use of traditional hydroxamic‐acid‐containing inhibitors, which rely on chelation to the conserved active‐site zinc ion. Here we review the literature on macrocyclic HDAC inhibitors obtained from natural sources and on structure–activity relationship studies inspired by these molecules, as well as on efforts aimed at fully synthetic macrocyclic HDAC inhibitors.