TY - JOUR
T1 - Natural and Synthetic Macrocyclic Inhibitors of the Histone Deacetylase Enzymes
AU - Maolanon, Alex
AU - Kristensen, Helle
AU - Leman, Luke
AU - Ghadiri, Reza
AU - Olsen, Christian Adam
N1 - © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
PY - 2017/1/3
Y1 - 2017/1/3
N2 - 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.
AB - 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.
U2 - 10.1002/cbic.201600519
DO - 10.1002/cbic.201600519
M3 - Journal article
C2 - 27748555
SN - 1439-4227
VL - 18
SP - 5
EP - 49
JO - ChemBioChem
JF - ChemBioChem
IS - 1
ER -
