Glucuronidation of Methylated Quercetin Derivatives: Chemical and Biochemical Approaches

• Published in: Journal of agricultural and food chemistry 2020-12, Vol.68 (50), p.14790-14807
• Main Authors: Docampo-Palacios, Maite L, Alvarez-Hernández, Anislay, Adiji, Olubu, Gamiotea-Turro, Daylin, Valerino-Diaz, Alexander B, Viegas, Luís P, Ndukwe, Ikenna E, de Fátima, Ângelo, Heiss, Christian, Azadi, Parastoo, Pasinetti, Giulio M, Dixon, Richard A
• Format: Article
• Language: English
• Subjects: Agriculture; Animals; Bioactive Constituents, Metabolites, and Functions; Brain - metabolism; Chemistry; Food Science & Technology; Glucuronides - chemistry; Glucuronides - metabolism; Glucuronosyltransferase - metabolism; Male; Molecular Structure; Quercetin - analogs & derivatives; Quercetin - chemistry; Quercetin - metabolism; Rats; Vitis - metabolism
• ISSN: 0021-8561; 1520-5118
• DOI: 10.1021/acs.jafc.0c04500

Botanical supplements derived from grapes are functional in animal model systems for the amelioration of neurological conditions, including cognitive impairment. Rats fed with grape extracts accumulate 3′-O-methyl-quercetin-3-O-β-d-glucuronide (3) in their brains, suggesting 3 as a potential therapeutic agent. To develop methods for the synthesis of 3 and the related 4′-O-methyl-quercetin-7-O-β-d-glucuronide (4), 3-O-methyl-quercetin-3′-O-β-d-glucuronide (5), and 4′-O-methyl-quercetin-3′-O-β-d-glucuronide (6), which are not found in the brain, we have evaluated both enzymatic semisynthesis and full chemical synthetic approaches. Biocatalysis by mammalian UDP-glucuronosyltransferases generated multiple glucuronidated products from 4′-O-methylquercetin, and is not cost-effective. Chemical synthetic methods, on the other hand, provided good results; 3, 5, and 6 were obtained in six steps at 12, 18, and 30% overall yield, respectively, while 4 was synthesized in five steps at 34% overall yield. A mechanistic study on the unexpected regioselectivity observed in the quercetin glucuronide synthetic steps is also presented.