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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• 作者：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 Altucci ; Carlo Gaetano ; Antonello Mai
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：February 25, 2016
• 年：2016
• 卷：59
• 期：4
• 页码：1471-1491
• 全文大小：897K
• ISSN：1520-4804

文摘

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.