1,4-Dihydropyridines Active on the SIRT1/AMPK Pathway Ameliorate Skin Repair and Mitochondrial Function and Exhibit Inhibition of Proliferation in Cancer Cells

Sergio Valente, Paolo Mellini, Francesco Spallotta, Vincenzo Carafa, Angela Nebbioso, Lucia Polletta, Ilaria Carnevale, Serena Saladini, Daniela Trisciuoglio, Chiara Gabellini, Maria Tardugno, Clemens Zwergel, Chiara Cencioni, Sandra Atlante, Sébastien Moniot, Clemens Steegborn, Roberta Budriesi, Marco Tafani, Donatella Del Bufalo, Lucia AltucciCarlo Gaetano, Antonello Mai

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1471-1491
Number of pages21
JournalJournal of Medicinal Chemistry
Volume59
Issue number4
DOIs
Publication statusPublished - Feb 25 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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