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

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Valente, Sergio ; Mellini, Paolo ; Spallotta, Francesco ; Carafa, Vincenzo ; Nebbioso, Angela ; Polletta, Lucia ; Carnevale, Ilaria ; Saladini, Serena ; Trisciuoglio, Daniela ; Gabellini, Chiara ; Tardugno, Maria ; Zwergel, Clemens ; Cencioni, Chiara ; Atlante, Sandra ; Moniot, Sébastien ; Steegborn, Clemens ; Budriesi, Roberta ; Tafani, Marco ; del Bufalo, Donatella ; Altucci, Lucia ; Gaetano, Carlo ; Mai, Antonello:
1,4-Dihydropyridines Active on the SIRT1/AMPK Pathway Ameliorate Skin Repair and Mitochondrial Function and Exhibit Inhibition of Proliferation in Cancer Cells.
In: Journal of Medicinal Chemistry. Bd. 59 (2016) Heft 4 . - S. 1471-1491.
ISSN 1520-4804
DOI: https://doi.org/10.1021/acs.jmedchem.5b01117

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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.