Ricerc@Sapienza

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.