Bispyridinium dienes: histone deacetylase inhibitors with selective activities
| Autor: | Angel R. de Lera, Annunziata Minichiello, Angela Nebbioso, Lucia Altucci, ‡,§ and, Marco Miceli, † Paula Rodríguez-Graña, Carlos Pérez-Balado |
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| Přispěvatelé: | CARLOS PEREZ, Balado, Nebbioso, Angela, PAULA RODRIGUEZ, Gra, Annunziata, Minichiello, Marco, Miceli, Altucci, Lucia, AND ANGEL R., DE LERA |
| Rok vydání: | 2007 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Macrocyclic Compounds Diene Stereochemistry medicine.drug_class Antineoplastic Agents Apoptosis Pyridinium Compounds chemistry.chemical_compound Structure-Activity Relationship HDAC inhibitors Tubulin Cell Line Tumor Drug Discovery medicine Humans Cancer biology Histone deacetylase 2 Histone deacetylase inhibitor Cell Cycle Epigenetic Acetylation Cell Differentiation HDAC4 HDAC1 Alkadienes Histone Deacetylase Inhibitors chemistry Biochemistry Enzyme inhibitor biology.protein Molecular Medicine Histone deacetylase |
| Zdroj: | Journal of medicinal chemistry. 50(10) |
| ISSN: | 0022-2623 |
| Popis: | A novel synthetic route to the cyclostellettamines 1 using as the key step a microwave-mediated macrocyclic ring-closing metathesis of precursors bispyridinium dienes 10 followed by catalytic hydrogenation has been developed. The open-chain bispyridinium dienes 10 showed uniformly higher histone deacetylase (HDAC) inhibitory potency than the natural products. Diene 10b inhibited HDAC1 and was inactive on HDAC4, whereas 10a showed a weak inhibition of HDAC1 and a higher activity on HDAC4. Neither 10b nor 10a inhibited isoforms HDAC2 and HDAC3. Cell cycle analysis, cell differentiation, and apoptosis as well as evaluation of the acetylation status of H3 lysine tails, up-regulation of p21WAF1/CIP1, and alpha-tubulin acetylation induced by the dienes 10 and cyclostellettamines 1 were also carried out on the human leukemia U937 cell line. These enzymatic and functional assays suggest that 10b is a HDAC1-selective inhibitor and 10a is a HDAC subclass IIa-selective inhibitor. |
| Databáze: | OpenAIRE |
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