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

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.