The Chemistry of Wine Polyphenolic C‐Glycosidic Ellagitannins Targeting Human Topoisomerase II

Abstract

Polyphenolic nonahydroxyterphenoyl-containing C-glycosidic oak ellagitannins are found in wine as a result of the aging of this beverage in oak-made barrels. Once in the slightly acidic wine (pH approximately 3-4), some of these complex natural products such as (-)-vescalagin (1), but not its C-1 epimer (-)-castalagin (2), can capture grape-derived nucleophilic entities such as ethanol, the flavanols catechin (10a) and epicatechin (10b), the anthocyanin oenin (13b), and the thiolic glutathione (16) to furnish condensation products with retention of configuration at the C-1 locus. A computer-aided rationale of this high diastereoselectivity is given. These condensation products can contribute to the modulation of organoleptic properties of the wine, as evidenced by the 23 nm bathochromic shift color absorbance observed with the novel oenin-based anthocyano-ellagitannin (15b). Hydrolysis of 1 under solvolytic conditions furnished another novel compound that we refer to as vescalene (21), in addition to the known (-)-vescalin (18). Of pharmacological importance is the fact that most of these found-in-wine water-soluble ellagitannin derivatives are much more potent than etoposide (VP-16) at inhibiting top2-mediated DNA decatenation in vitro (top2=topoisomerase II)). The known (-)-vescalin (18) and the novel vescalene (21) fully inhibited top2 at 10 microM concentration!

The Polyphenolic Ellagitannin Vescalagin Acts As a Preferential Catalytic Inhibitor of the α Isoform of Human DNA Topoisomerase II

“…1) (Quideau et al, 2011). These derivatives were prepared from vescalagin or castalagin that was extracted and purified from oak wood according to previously published procedures (Quideau et al, 2003(Quideau et al, , 2004(Quideau et al, , 2005. We first tested the effect of these ellagitannins on the catalytic activity of purified human Top2␣ and Top2␤ as measured by the in vitro decatenation of kinetoplast DNA.…”

“…In the search for new topoisomerase II inhibitors originating from plants, a previous study investigated the ability of 60 compounds from the four main classes of tannins, gallotannins, ellagitannins, complex tannins, and condensed tannins, to inhibit human topoisomerase II in vitro and identified 36 derivatives that could inhibit Top2 with a higher potency than that of etoposide . More recently, we also found that new polyphenolic C-glucosidic ellagitannins isolated from wine aged in oak barrels could also inhibit Top2 with high potency (Quideau et al, 2005). However, the specificity of these ellagitannins toward Top2␣ or Top2␤ was never addressed.…”

“…The natural C-glucosidic ellagitannin vescalagin and all its analogous congeners or derivatives used in this study were extracted and purified from Quercus robur heartwood or hemisynthesized and purified as described previously (Quideau et al, 2004(Quideau et al, , 2005. Etoposide and all other chemicals were purchased from Sigma-Aldrich (L'Isle d'Abeau Chesnes, France) unless otherwise stated.…”

“…However, it was not reported whether they could specifically target one of the two isoforms of Top2. In this study, we investigated such selectivity for vescalagin and other polyphenolic nonahydroxyterphenoyl (NHTP)-containing C-glucosidic ellagitannins, which are found in wine aged in oak-made barrels and were shown to inhibit Top2 in vitro (Quideau et al, 2005). We show that vescalagin preferentially inhibits Top2␣-mediated decatenation of kDNA in vitro in a redox-independent manner, suggesting a mechanism other than that of etoposide or quinonebased agents such as benzoquinone.…”

C-glucosidic ellagitannin concentrations variability during the years in Syrah wines from Languedoc vineyard

“…The formation of flavano-ellagitannins (9-12) and the ß-1-O-ethylvescalagin (13) in red wines aged in oak barrels has been reported [14][15][16][17][18] (Fig. 1).…”