Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 59, Issue 4, Pages 1471-1491Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b01117
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Funding
- FIRB [RBFR10ZJQT]
- IIT-Sapienza Project
- FP7 Projects [BLUEPRINT/282510, A-PARADDISE/602080]
- AIRC [IG14100]
- Fondazione Umberto Veronesi Fellowship
- [RF-2010-2318330]
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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 mu M and increased H4K16 deacetylation, suggesting a possible role for SIRT1 activators in cancer therapy.
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