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8644016 
Journal Article 
Glucuronidation of Methylated Quercetin Derivatives: Chemical and Biochemical Approaches 
Docampo-Palacios, ML; Alvarez-Hernandez, A; Adiji, O; Gamiotea-Turro, D; Valerino-Diaz, AB; Viegas, LP; Ndukwe, IE; De Fatima, A; Heiss, C; Azadi, P; Pasinetti, GM; Dixon, RA 
2020 
Yes 
Journal of Agricultural and Food Chemistry
ISSN: 0021-8561
EISSN: 1520-5118 
68 
50 
14790-14807 
English 
33289379 
WOS:000600204700008 
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.