Docampo-Palacios, Maite L.Alvarez-Hernández, AnislayAdiji, OlubuGamiotea-Turro, Daylin [UNESP]Valerino-Diaz, Alexander B. [UNESP]Viegas, Luís P.Ndukwe, Ikenna E.De Fátima, ÂngeloHeiss, ChristianAzadi, ParastooPasinetti, Giulio M.Dixon, Richard A.2021-06-252021-06-252020-12-16Journal of Agricultural and Food Chemistry, v. 68, n. 50, p. 14790-14807, 2020.1520-51180021-8561http://hdl.handle.net/11449/205611Botanical 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.14790-14807engglucuronidationglucuronosyltransferasesintrinsic reaction coordinatemethoxylated quercetinmolecular modellingphase II metabolitessemi-synthesisArtigo10.1021/acs.jafc.0c045002-s2.0-85097896308