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Updated: Jun 5, 2026
Simultaneous Measurement of HDAC1 and HDAC6 Activity in HeLa Cells Using UHPLC-MS
Published on: August 10, 2017
Structure and property based design, synthesis and biological evaluation of γ-lactam based HDAC inhibitors
Eunhyun Choi1, Chulho Lee, Jung Eun Park
1Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea.
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.
Insights
New histone deacetylase (HDAC) inhibitors with a smaller gamma-lactam core demonstrate enhanced potency for cancer treatment. These novel HDAC inhibitors offer improved efficacy compared to previous delta-lactam analogues.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Cancer Research
Background:
- Histone deacetylases (HDACs) regulate gene expression and are crucial for cancer cell survival.
- HDACs are epigenetic targets for cancer therapy, with inhibitors showing promise.
- Previous delta-lactam HDAC inhibitors exhibited potent anti-cancer activity.
Purpose of the Study:
- To design and synthesize novel gamma-lactam core HDAC inhibitors.
- To optimize biological activity and properties of HDAC inhibitors.
- To investigate the structure-activity relationship for improved HDAC inhibition.
Main Methods:
- Quantitative Structure-Activity Relationship (QSAR) analysis of delta-lactam inhibitors.
- Design and synthesis of gamma-lactam based HDAC inhibitors.
- Introduction of phenyl, naphthyl, and thiophenyl cap groups.
Main Results:
- QSAR suggested smaller core structures are more active due to enzyme pocket fit.
- Gamma-lactam HDAC inhibitors demonstrated higher potency than delta-lactam analogues.
- Hydrophobic and bulky cap groups enhanced HDAC inhibition potency.
Conclusions:
- The smaller gamma-lactam core is a more effective scaffold for HDAC inhibitors.
- Novel gamma-lactam HDAC inhibitors show significant potential for cancer therapy.
- Optimized cap groups contribute to increased potency through hydrophobic interactions.
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