title: Study of 1,4-dihydropyridine structural scaffold: discovery of novel sirtuin activators and inhibitors.
abstract: 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.
authors: Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi di Roma La Sapienza, Roma, Italy. antonello.mai@uniroma1.it
authors: Antonello
authors: A
authors: Mai
authors: Sergio
authors: S
authors: Valente
authors: Sarah
authors: S
authors: Meade
authors: Vincenzo
authors: V
authors: Carafa
authors: Maria
authors: M
authors: Tardugno
authors: Angela
authors: A
authors: Nebbioso
authors: Andrea
authors: A
authors: Galmozzi
authors: Nico
authors: N
authors: Mitro
authors: Emma
authors: E
authors: De Fabiani
authors: Lucia
authors: L
authors: Altucci
authors: Aleksey
authors: A
authors: Kazantsev
mesh_terms: D000480:Alkynes / Q000737:chemistry; D000588:Amines / Q000737:chemistry; D000818:Animals; D001547:Benzaldehydes / Q000737:chemistry; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000201:enzymology; D051379:Mice; D032446:Myoblasts / Q000166:cytology / Q000201:enzymology; D011422:Propionates / Q000737:chemistry; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D037761:Sirtuins / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D000480:Alkynes; D000588:Amines; D001547:Benzaldehydes; D004791:Enzyme Inhibitors; D011422:Propionates; D011725:Pyridines; D037761:Sirtuins; C011537:propiolic acid; C032175:benzaldehyde