Glucuronidation of Methylated Quercetin Derivatives: Chemical and Biochemical Approaches

• Autor(a) principal: Docampo-Palacios, Maite L.
• Data de Publicação: 2020
• Outros Autores: Alvarez-Hernández, Anislay, Adiji, Olubu, Gamiotea-Turro, Daylin [UNESP], Valerino-Diaz, Alexander B. [UNESP], Viegas, Luís P., Ndukwe, Ikenna E., De Fátima, Ângelo, Heiss, Christian, Azadi, Parastoo, Pasinetti, Giulio M., Dixon, Richard A.
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Institucional da UNESP
• Texto Completo: http://dx.doi.org/10.1021/acs.jafc.0c04500; http://hdl.handle.net/11449/205611
• topic: glucuronidation; glucuronosyltransferases; intrinsic reaction coordinate; methoxylated quercetin; molecular modelling; phase II metabolites; semi-synthesis

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.