Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 21, Issue 4, Pages 1218-1221Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2010.12.079
Keywords
Histone deacetylase; HDAC; Inhibitor; Isoform; Anticancer; In vitro activity; Docking study; ADME
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Funding
- National Research Foundation [2009-0092966]
- Korea Research WCU [R31-2008-000-10086-0]
- Brain Korea 21 project, Republic of Korea
- National Research Foundation of Korea [2009-0092966] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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 delta-lactam core HDAC inhibitors which showed potent HDAC inhibitory activities as well as cancer cell growth inhibitory activities. Through QSAR study of the delta-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 gamma-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, gamma-lactam based HDAC inhibitors showed more potent than delta-lactam analogues. (C) 2010 Elsevier Ltd. All rights reserved.
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