Glucuronidation of Methylated Quercetin Derivatives: Chemical and Biochemical Approaches
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Data
2020-12-16
Autores
Docampo-Palacios, Maite L.
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
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Resumo
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.
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glucuronidation, glucuronosyltransferases, intrinsic reaction coordinate, methoxylated quercetin, molecular modelling, phase II metabolites, semi-synthesis
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Journal of Agricultural and Food Chemistry, v. 68, n. 50, p. 14790-14807, 2020.