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Title 

Discovery of pyridone-based histone deacetylase inhibitors: approaches for metabolic stability

Authors 

M ChoE ChoiJ S YangC LeeJ J SeoB S KimSoo Jin OhH M KimK LeeS K ParkH J KwonG Han

Publisher 

Wiley-VCH Verlag

Issue Date 

2013

Citation 

ChemMedChem, vol. 8, no. 2, pp. 272-279

Keywords 

ConjugationDrug designHistone deacetylasesInhibitorsMetabolismPyridones

Abstract 

Histone deacetylases (HDACs) are important enzymes in epigenetic regulation and are therapeutic targets for cancer. Most zinc-dependent HDACs induce proliferation, dedifferentiation, and anti-apoptotic effects in cancer cells. We designed and synthesized a new series of pyridone-based HDAC inhibitors that have a pyridone ring in the core structure and a conjugated system with an olefin connecting the hydroxamic acid moiety. Consequently, most of the selected pyridone-based HDAC inhibitors showed similar or higher inhibition profiles in addition to remarkable metabolic stability against hydrolysis relative to the corresponding lactam-based HDAC inhibitors. Furthermore, the selectivity of the novel pyridine-based compounds was evaluated across all of the HDAC isoforms. One of these compounds, (E)-N-hydroxy-3-{1-[3-(naphthalen-2-yl)propyl]-2-oxo-1,2-dihydropyridin-3-yl}acrylamide, exhibited the highest level of HDAC inhibition (IC50=0.07μM), highly selective inhibition of classI HDAC1 and classII HDAC6 enzymes, metabolic stability in mouse liver microsomal studies, and effective growth inhibition of various cancer cell lines. Docking studies indicated that a long alkyl linker and bulky hydrophobic cap groups affect invitro activities. Overall, the findings reported herein regarding pyridone-based HDAC inhibitors can be used to guide future research efforts to develop new and effective anticancer therapeutics.

ISSN 

1860-7187

Link 

http://dx.doi.org/10.1002/cmdc.201200529

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2017-04-19


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