The Chemistry of Wine Polyphenolic <i>C</i>‐Glycosidic Ellagitannins Targeting Human Topoisomerase II

TLDR

Wine aging in oak barrels generates polyphenolic C‑glycosidic ellagitannins such as vescalagin and castalagin. The study aims to provide a computer‑aided rationale for the high diastereoselectivity observed when these ellagitannins react with wine‑derived nucleophiles. In slightly acidic wine (pH 3–4), vescalagin captures nucleophiles—including ethanol, catechin, epicatechin, oenin, and glutathione—to form condensation products that retain the C‑1 configuration. These condensation products alter wine color (a 23 nm bathochromic shift), yield novel compounds such as vescalene, and exhibit potent inhibition of human topoisomerase II—more effective than etoposide and fully inhibiting the enzyme at 10 µM.

Abstract

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∼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 ( 10 a ) and epicatechin ( 10 b ), the anthocyanin oenin ( 13 b ), 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 ( 15 b ). 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 μ M concentration!