title: 1,4-Dihydropyridines Active on the SIRT1/AMPK Pathway Ameliorate Skin Repair and Mitochondrial Function and Exhibit Inhibition of Proliferation in Cancer Cells.
abstract: Modulators of sirtuins are considered promising therapeutic targets for the treatment of cancer, cardiovascular, metabolic, inflammatory, and neurodegenerative diseases. Here we prepared new 1,4-dihydropyridines (DHPs) bearing changes at the C2/C6, C3/C5, C4, or N1 position. Tested with the SIRTainty procedure, some of them displayed increased SIRT1 activation with respect to the prototype 3a, high NO release in HaCat cells, and ameliorated skin repair in a mouse model of wound healing. In C2C12 myoblasts, two of them improved mitochondrial density and functions. All the effects were reverted by coadministration of compound C (9), an AMPK inhibitor, or of EX-527 (10), a SIRT1 inhibitor, highlighting the involvement of the SIRT1/AMPK pathway in the action of DHPs. Finally, tested in a panel of cancer cells, the water-soluble form of 3a, compound 8, displayed antiproliferative effects in the range of 8-35 μM and increased H4K16 deacetylation, suggesting a possible role for SIRT1 activators in cancer therapy.
authors.affiliation: Department of Drug Chemistry and Technologies, Sapienza University of Rome , P. le A. Moro 5, 00185 Rome, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Valente
authors.affiliation: Department of Drug Chemistry and Technologies, Sapienza University of Rome , P. le A. Moro 5, 00185 Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Mellini
authors.affiliation: Division of Cardiovascular Epigenetics, Department of Cardiology, Goethe University , Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Francesco
authors.initials: F
authors.lastname: Spallotta
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples , Vico L. De Crecchio 7, 80138 Naples, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Carafa
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples , Vico L. De Crecchio 7, 80138 Naples, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Nebbioso
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome , Viale Regina Elena 324, 00161 Rome, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Polletta
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome , Viale Regina Elena 324, 00161 Rome, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Carnevale
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome , Viale Regina Elena 324, 00161 Rome, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Saladini
authors.affiliation: Regina Elena National Cancer Institute , Via Elio Chianesi, 53, 00144 Rome, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Trisciuoglio
authors.affiliation: Regina Elena National Cancer Institute , Via Elio Chianesi, 53, 00144 Rome, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Gabellini
authors.affiliation: Department of Drug Chemistry and Technologies, Sapienza University of Rome , P. le A. Moro 5, 00185 Rome, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Tardugno
authors.affiliation: Department of Drug Chemistry and Technologies, Sapienza University of Rome , P. le A. Moro 5, 00185 Rome, Italy.
authors.forename: Clemens
authors.initials: C
authors.lastname: Zwergel
authors.affiliation: Division of Cardiovascular Epigenetics, Department of Cardiology, Goethe University , Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cencioni
authors.affiliation: Division of Cardiovascular Epigenetics, Department of Cardiology, Goethe University , Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Atlante
authors.affiliation: Department of Biochemistry, University of Bayreuth ; 95447 Bayreuth, Germany.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Moniot
authors.affiliation: Department of Biochemistry, University of Bayreuth ; 95447 Bayreuth, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Steegborn
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna , Via Zamboni 33, 40126 Bologna, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Budriesi
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome , Viale Regina Elena 324, 00161 Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Tafani
authors.affiliation: Regina Elena National Cancer Institute , Via Elio Chianesi, 53, 00144 Rome, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Del Bufalo
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples , Vico L. De Crecchio 7, 80138 Naples, Italy.|Institute of Genetics and Biophysics, IGB, Adriano Buzzati Traverso , Via P. Castellino 111, 80131 Naples, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Altucci
authors.affiliation: Division of Cardiovascular Epigenetics, Department of Cardiology, Goethe University , Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Carlo
authors.initials: C
authors.lastname: Gaetano
authors.affiliation: Department of Drug Chemistry and Technologies, Sapienza University of Rome , P. le A. Moro 5, 00185 Rome, Italy.|Pasteur Institute, Cenci-Bolognetti Foundation, Sapienza University of Rome , P. le A. Moro 5, 00185 Rome, Italy.
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004095:Dihydropyridines / Q000737:chemistry / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism*; D012867:Skin / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D004095:Dihydropyridines; C038806:1,4-dihydropyridine; D055372:AMP-Activated Protein Kinases; D056564:Sirtuin 1