Terpenylated coumarins as SIRT1 activators isolated from ailanthus altissima

Four new terpenylated coumarins (1-4) were isolated from the stem bark of Ailanthus altissima by bioactivity-guided fractionation using an in vitro SIRT1 deacetylation assay. Their structures were identified as (2′R,3′R)- 7-(2′,3′-dihydroxy-3′,7′-dimethylocta-6′-enyloxy) -6,8-dimethoxycoumarin (1), 6,8-dimethoxy-7-(3′,7′-dimethylocta- 2′,6′-dienyloxy)coumarin (2), (2′R,3′R,6′R)-7- (2′,3′-dihydroxy-6′,7′-epoxy-3′, 7′-dimethyloctaoxy)-6,8-dimethoxycoumarin (3), and (2′R,3′R, 4′S,5′S)-6,8-dimethoxy-7-(3′,7′-dimethyl-4′, 5′-epoxy-2′-hydroxyocta-6′-enyloxy)coumarin (4). Compounds 1-4 strongly enhanced SIRT1 activity in an in vitro SIRT1-NAD/NADH assay and an in vivo SIRT1-p53 luciferase assay. These compounds also increased the NAD-to-NADH ratio in HEK293 cells. The present results suggest that terpenylated coumarins from A. altissima have a direct stimulatory effect on SIRT1 deacetylation activity and may serve as lead molecules for the treatment of some age-related disorders.