Study of 1,4-Dihydropyridine Structural Scaffold: Discovery of Novel Sirtuin Activators and Inhibitors
| Autor: | Vincenzo Carafa, Sarah Meade, Maria Tardugno, Antonello Mai, Sergio Valente, Lucia Altucci, Aleksey G. Kazantsev, Angela Nebbioso, Nico Mitro, Emma De Fabiani, Andrea Galmozzi |
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| Přispěvatelé: | Mai, A, Valente, S, Meade, S, Carafa, V, Tardugno, M, Nebbioso, Angela, Galmozzi, A, Mitro, N, DE FABIANI, E, Altucci, Lucia, Kazantsev, A. |
| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Pyridines
SIRT2 01 natural sciences Myoblasts 03 medical and health sciences Mice Cell Line Tumor Drug Discovery medicine Animals Humans Sirtuins Amines Enzyme Inhibitors 030304 developmental biology chemistry.chemical_classification 0303 health sciences biology 010405 organic chemistry Dihydropyridine Mesenchymal Stem Cells Small molecule 0104 chemical sciences 3. Good health Enzyme Activation Enzyme chemistry Biochemistry Enzyme inhibitor Alkynes Benzaldehydes Sirtuin biology.protein Molecular Medicine Histone deacetylase NAD+ kinase Propionates medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry |
| Popis: | NAD(+)-dependent sirtuin deacetylases have emerged as potential therapeutic targets for treatment of human illnesses such as cancer, metabolic, cardiovascular, and neurodegenerative diseases. The benefits of sirtuin modulation by small molecules have been demonstrated for these diseases. In contrast to the discovery of inhibitors of SIRT1, -2, and -3, only activators for SIRT1 are known. Here, we rationalized the potential of the previously unexplored dihydropyridine scaffold in developing sirtuin ligands, thus we prepared a series of 1,4-dihydropyridine-based derivatives 1-3. Assessment of their SIRT1-3 deacetylase activities revealed the importance of the substituent at the N1 position of the dihydropyridine structure on sirtuin activity. Placement of cyclopropyl, phenyl, or phenylethyl groups at N1 conferred nonselective SIRT1 and SIRT2 inhibition activity, while a benzyl group at N1 conferred potent SIRT1, -2, and -3 activation. Senescence assays performed on hMSC and mitochondrial function studies conducted with murine C2C12 myoblasts confirmed the compounds' novel and unique SIRT-activating properties. |
| Databáze: | OpenAIRE |
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