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

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Title
Structure and property based design, synthesis and biological evaluation of gamma-lactam based HDAC inhibitors
Author(s)
E Choi; C Lee; J E Park; J J Seo; M Cho; Jong Soon Kang; Hwan Mook Kim; Song Kyu Park; Kiho Lee; G Han
Bibliographic Citation
Bioorganic & Medicinal Chemistry Letters, vol. 21, no. 4, pp. 1218-1221
Publication Year
2011
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.
Keyword
ADMEAnticancerDocking studyHDACHistone deacetylaseIn vitro activityInhibitorIsoform
ISSN
0960-894X
Publisher
Elsevier
DOI
http://dx.doi.org/10.1016/j.bmcl.2010.12.079
Type
Article
Appears in Collections:
Ochang Branch Institute > Division of Bioinfrastructure > Laboratory Animal Resource Center > 1. Journal Articles
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