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Mercaptoamide-based non-hydroxamic acid type histone deacetylase inhibitors
Sampath-Kumar Anandan1, John S Ward, Richard D Brokx
1Miikana Therapeutics Inc, 6519 Dumbarton Circle, Fremont, CA 94555, USA. skumar@miikana.com <skumar@miikana.com>
Bioorganic & Medicinal Chemistry Letters
|April 6, 2005
Summary
New mercaptoamide compounds show promise as anti-cancer agents by inhibiting histone deacetylases (HDAC). Researchers designed these non-hydroxamate HDAC inhibitors, with some compounds demonstrating low micromolar activity.
Area of Science:
- Medicinal Chemistry
- Biochemistry
- Cancer Research
Background:
- Histone deacetylase (HDAC) inhibitors are a developing class of anti-cancer drugs.
- The SAHA scaffold is a known hydroxamic acid-based structure used in HDAC inhibitor development.
Purpose of the Study:
- To design and synthesize novel non-hydroxamate HDAC inhibitors.
- To explore mercaptoamide functionality as a bidentate zinc chelator for HDAC inhibition.
- To evaluate the HDAC inhibitory activity of newly synthesized mercaptoamide compounds.
Main Methods:
- Design of mercaptoamide compounds incorporating a bidentate zinc chelator.
- Synthesis of two series of mercaptoamides (compounds 2 and 3) with varied spacer lengths.
- In vitro evaluation of HDAC inhibitory activity for synthesized compounds.
Main Results:
- Successful synthesis of mercaptoamide compounds 2 and 3.
- Identification of specific mercaptoamides (2e, 3b, and 3d) exhibiting low micromolar HDAC inhibition.
- Demonstration of mercaptoamide functionality as a viable alternative to hydroxamates for HDAC inhibition.
Conclusions:
- Mercaptoamides represent a promising alternative scaffold for developing novel HDAC inhibitors.
- Compounds 2e, 3b, and 3d show potential as anti-cancer agents due to their HDAC inhibitory activity.
- Further investigation into mercaptoamide-based HDAC inhibitors is warranted.