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Title 

Structure and property based design, synthesis and biological evaluation of gamma-lactam based HDAC inhibitors

Authors 

E ChoiC LeeJ E ParkJ J SeoM ChoJong Soon KangHwan Mook KimSong Kyu ParkKiho LeeG Han

Publisher 

Elsevier

Issue Date 

2011

Citation 

Bioorganic & Medicinal Chemistry Letters, vol. 21, no. 4, pp. 1218-1221

Keywords 

ADMEAnticancerDocking studyHDACHistone deacetylaseIn vitro activityInhibitorIsoform

Abstract 

Histone deacetylases (HDACs) are involved in post-translational modification and gene expression. Cancer cells recruited amounts of HDACs for their survival by epi-genetic down regulation of tumor suppressor genes. HDACs have been the promising targets for treatment of cancer, and many HDAC inhibitors have been investigated nowadays. In previous study, we synthesized δ-lactam core HDAC inhibitors which showed potent HDAC inhibitory activities as well as cancer cell growth inhibitory activities. Through QSAR study of the δ-lactam based inhibitors, the smaller core is suggested as more active than larger one because it fits better in narrow hydrophobic tunnel of the active pocket of HDAC enzyme. The smaller γ-lactam core HDAC inhibitors were designed and synthesized for biological and property optimization. Phenyl, naphthyl and thiophenyl groups were introduced as the cap groups. Hydrophobic and bulky cap groups increase potency of HDAC inhibition because of hydrophobic interaction between HDAC and inhibitors. In overall, γ-lactam based HDAC inhibitors showed more potent than δ-lactam analogues.

ISSN 

0960-894X

Link 

http://dx.doi.org/10.1016/j.bmcl.2010.12.079

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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