Design and synthesis of novel and highly-active pan-histone deacetylase (pan-HDAC) inhibitors
| Autor: | Toshihiko Tashima, Hidehiko Kodama, Hiroaki Murata |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Clinical Biochemistry
Pharmaceutical Science Hydroxamic Acids Biochemistry Histone Deacetylases chemistry.chemical_compound Structure-Activity Relationship Drug Discovery Animals Molecular Biology Hydroxamic acid Dose-Response Relationship Drug Molecular Structure Histone deacetylase 2 Organic Chemistry HDAC9 Biological activity HDAC8 HDAC6 HDAC4 Rats Histone Deacetylase Inhibitors chemistry Liver Drug Design Molecular Medicine Histone deacetylase |
| Zdroj: | Bioorganicmedicinal chemistry. 22(14) |
| ISSN: | 1464-3391 |
| Popis: | Histone deacetylase (HDAC) inhibitions are known to elicit anticancer effects. We designed and synthesized several HDAC inhibitors. Among these compounds, compound 40 exhibited a more than 10-fold stronger inhibitory activity compared with that of suberoylanilide hydroxamic acid (SAHA) against each human HDAC isozyme in vitro (IC50 values of 40: HDAC1, 0.0038μM; HDAC2, 0.0082μM; HDAC3, 0.015μM; HDAC8, 0.0060μM; HDAC4, 0.058μM; HDAC9, 0.0052μM; HDAC6, 0.058μM). The dose of the administered HDAC inhibitors that contain hydroxamic acid as the zinc-binding group may be reduced by 40. Because the carbostyril subunit is a time-tested structural component of drugs and biologically active compounds, 40 most likely exhibits good absorption, distribution, metabolism, excretion, and toxicity (ADMET). Thus, compound 40 is expected to be a promising therapeutic agent or chemical tool for the investigation of life process. |
| Databáze: | OpenAIRE |
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