Modulation of Sirtuins activity is retained a promising therapeutic strategy for the treatment of cancer, cardiovascular, metabolic, inflammatory, and neurodegenerative diseases. Recently we reported the discovery of a series of 1,4-dihydropyridines (DHPs) able to activate SIRT1 in enzyme assays and to reduce up to 40% senescent cells in human mesenchymal stem cells, to increase mitochondrial function in murine C2C12 myoblasts, and to stimulate proliferation in human keratinocyte HaCaT cells via activation of endothelial nitric oxide synthase and subsequent nitric oxide increased production. Moreover, selected compounds were able to accelerate tissue renewal in a mouse model of skin repair, and displayed anticancer effect in different cancer cell lines. From the last series of DHPs, two compounds bearing an acyl function at the N1-position of the DHP scaffold (MC2791 and MC2789) displayed selective activation of SIRT3 over SIRT1, -2 and -5. This specific SIRT3 activation was confirmed by mass spectrometry analysis as well as by SIRT3-activators binding affinity experiments. Prompted by these results, we will apply some modifications at the N1 position on these hit compounds with the aim to improve their potency and isoform selectivity.
The natural polyphenol resveratrol was the first SIRT1 activator described. Its administration extends lifespan in yeast, Caenorhabditis elegans, Drosophila, fishes, and bees. Mice treated with resveratrol displays improved mitochondrial functions and protection against high-fat diet-induced obesity, while in obese mice, treatment with resveratrol leads to an increased health span and lifespan20. Over the past years, the effective SIRT1 activation by resveratrol and other SRT compounds has been highly debated, because only the use in the enzyme based assays with labelled substrates allowed to see activation, whereas in the presence of natural substrates no activation was observed21. However, direct SIRT1 activation by resveratrol has been confirmed later, and it has been shown that there are subtle structural and positional requirements to detect SIRT1 activation with some of its natural substrates (e.g., FOXO3a and PGC1alpha)19 and finally the co-crystal structure of a mini-h SIRT1-activator complex was solved15. Our research group developed the 1,4 DHP scaffold in 2009 as a new chemotype for SIRT activation. Selected DHPs induced high NO release in HaCat cells, and ameliorated skin repair in a mouse model of wound healing. In murine myoblasts, they improved mitochondrial density and functions through activation of the SIRT1/AMPK axis. In addition, a water-soluble DHP analogue displayed antiproliferative action and increased H4K16ac deacetylation in a panel of cancer cells at low micromolar concentrations22. Very recently, the cardiac anti-hypertrophic effects of the natural compound honokiol were reported to depend on pharmacological activation and increased level of SIRT316. The substrates of SIRT3 include a number of different enzymes, which serve unique and critical functions regulating metabolism, cell survival and longevity. Indeed, increased SIRT3 level was associated to extended humans lifespan, whereas decreased enzymatic activity of SIRT3 has been related to metabolic syndrome, highlighting a role of SIRT3 in regulating human aging. These studies suggest that higher SIRT3 intracellular activity would be a strategy to fight many diseases depending on SIRT3 deficiency23,24,25. In a recent study by our group26 the potential of the 1,4-DHP scaffold in developing for different Sirtuin isoform ligands was further investigated to disclose the importance of the substituent at the N1 position of the dihydropyridine structure (fig 1) for Sirtuins modulation. In particular, while the presence of a benzyl group at N1 position conferred potent SIRT1 activation, the replacement of the N1-benzyl with the N1-benzoyl or N1-3,4,5-trimethoxybenzoyl moiety (MC2791 and MC2789 respectively, fig. 1) shifted the biochemical activation from Sirt1 to SIRT3, thus providing the first-in-class synthetic, specific SIRT3 activators. Starting from these findings, a following up study addressed to deeply investigate the effects of these novel DHPs as SIRT3a would be a useful opportunity to better understand the potential biological/preclinical role of SIRT3 for the future treatment of metabolic- or aging-related diseases.
References
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22. Mai A. et al., J Med Chem. 2009;52(17):5496-504
23. Hirschey M.D et al., Nature 2010;464:121-125
24. Alcendor R.R et al., Circ. Res. 2004; 95, 971-980
25. Pillai J.B et al., J. Biol. Chem. 2005; 280, 43121-43130
26. Valente S. et al., J. Med. Chem. 2016, 59, 1471-1491