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

Eunhyun Choi, Chulho Lee, Jung Eun Park, Jeong Jea Seo, Misun Cho, Jong Soon Kang, Hwan Mook Kim, Song Kyu Park, Kiho Lee, Gyoonhee Han

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39 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1218-1221
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Issue number4
Publication statusPublished - 2011 Feb 15

Bibliographical note

Funding Information:
This research was supported by National Research Foundation ( 2009-0092966 ), Korea Research WCU grant ( R31-2008-000-10086-0 ) and Brain Korea 21 project, Republic of Korea.

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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