Effect of Resveratrol Dimers and Tetramers Isolated from Vitaceous and Dipterocarpaceous Plants on Human SIRT1 Enzyme Activity

Abstract

SIRT1 is a mammalian ortholog of the yeast enzyme Sir2, which is an NAD +-dependent deacetylase of histones, p53, FOXO, NF-κB, PGC-1α, and other transcription factors. The Sir2 protein is reported as a longevity protein in yeast. Resveratrol, a polyphenol isolated from various types of plant families, particularly the Vitaceae family, is a known naturally occurring SIRT1 activator. In this study, we evaluated the effects of four types of resveratrol dimers and four types of tetramers isolated from vitaceous plants, and one type of resveratrol tetramer isolated from a dipterocarpaceous plant on purified human SIRT1 enzyme activity. Of the resveratrol dimers examined, (+)-ε-viniferin and pallidol exhibited no effect on SIRT1 enzyme activity, whereas (+)-ampelopsin B and (−)-ampelopsin F showed inhibitory activity on SIRT1. However, all the resveratrol tetramers examined, i.e., (+)-vitisin A, (−)-vitisin B, (+)-hopeaphenol, (−)-hopeaphenol, and (−)-isohopeaphenol markedly inhibited the human SIRT1 enzyme activity. (+)-Hopeaphenol exhibited the most potent inhibitory activity, which was comparable with that exhibited by a known SIRT1 inhibitor suramin. Since SIRT1 inhibitors reportedly possess anticancer activity, (+)-hopeaphenol and other resveratrol oligomers can be used as a seed compound for anticancer drugs.

Structural analysis of the inhibitory effects of polyphenols, (+)‐hopeaphenol and (−)‐isohopeaphenol, on human SIRT1

“…Previously we showed that several kinds of resveratrol tetramers exerted inhibitory activity against purified hSIRT1. (+)‐HP exhibited the most potent inhibitory activity among all examined tetramers . In this study, we focused on the inhibition of hSIRT1 by (+)‐HP and its stereoisomer (−)‐iHP.…”

“…Recombinant hSIRT1 was produced using the E. coli BL21 (DE3) bacterial expression system by transforming the bacteria with a pET‐14b plasmid vector harboring the hSIRT1 cDNA. A recombinant 6 x His‐tagged hSIRT1 fusion protein was produced and purified to homogeneity using a Ni 2+ ‐chelating affinity column (HisTrap™ HP, GE Healthcare) as previously described . The protein purity was confirmed by 7.5% SDS‐polyacrylamide gel electrophoresis .…”

“…Recently, we isolated various polyphenols from Vitaceae plants, which were composed of a resveratrol unit, and determined their chemical structures . Some of these compounds, especially the resveratrol tetramers, (+)‐hopeaphenol ((+)‐HP)) and (−)‐isohopeaphenol ((−)‐iHP), inhibited the enzymatic activity of purified human sirtuin 1 (hSIRT1) . The present work uses experimental and computational approaches to understand the interactions between the two inhibitors and hSIRT1 protein.…”

Exploration of stilbenoid trimers as potential inhibitors of sirtuin1 enzyme using a molecular docking and molecular dynamics simulation approach

“…16 Additionally, stilbenoid derivatives showed SIRT1 (IC 50 mM) enzyme inhibitory activity, such as stilbenoid dimer ((À)-ampelopsin F: 24.4 mM) and stilbenoid tetramer ((+)-vitisin A: 22.0 mM, (À)-vitisin B: 21.1 mM, (+)-hopeaphenol: 3.45 mM, (À)-hopeaphenol: 18.1 mM, and (À)-isohopeaphenol: 21.6 mM). 17 Stilbenoid derivatives obtained from natural products are one of the solutions to get potential inhibitors against cancer. 18 Stilbenoid derivatives are a class of polyphenol compounds have known to inhibit the SIRT1 enzyme.…”

“…18 Stilbenoid derivatives are a class of polyphenol compounds have known to inhibit the SIRT1 enzyme. 17,19 Stilbenoid derivatives such as stilbenoid trimers isolated in the Dryobalanops 20,21 and Vitis labrusca 22 plants, widely distributed in Indonesia and Malaysia. Structurally, the stilbenoid trimers consist of three resveratrol monomers, which are linked by cyclic 2,3-dihydrofuran.…”