Efficient Chemical Synthesis of (Epi)catechin Glucuronides: Brain-Targeted Metabolites for Treatment of Alzheimer’s Disease and Other Neurological Disorders

Abstract

Grape seed extract (GSE) is rich in flavonoids and has been recognized to possess human health benefits. Our group and others have demonstrated that GSE is able to attenuate the development of Alzheimer's disease (AD). Moreover, our results have disclosed that the anti-Alzheimer's benefits are not directly/solely related to the dietary flavonoids themselves, but rather to their metabolites, particularly to the glucuronidated ones. To facilitate the understanding of regioisomer/stereoisomer-specific biological effects of (epi)catechin glucuronides, we here describe a concise chemical synthesis of authentic standards of catechin and epicatechin metabolites 3−12. The synthesis of glucuronides 9 and 12 is described here for the first time. The key reactions employed in the synthesis of the novel glucuronides 9 and 12 include the regioselective methylation of the 4′-hydroxyl group of (epi)catechin (≤1.0/99.0%; 3′-OMe/4′-OMe) and the regioselective deprotection of the tert-butyldimethylsilyl (TBS) group at position 5 (yielding up to 79%) over the others (3, 7 and 3′ or 4′).

Antifungal compounds of Chinese prickly ash against drug-resistant Candida albicans

“…29 known compounds were isolated and identified as (-)qin bun amide A ( 1 ) ( Tian et al, 2016 ), qin bun amide B ( 2 ) ( Tian et al, 2016 ), γ -sanshoöl ( 3 ) ( Yasuda, Takeya, & Itokawa, 1981 ), (-)-asarinin ( 4 ) ( Joonseok et al, 2010 ), (-)-kobusin ( 5 ) (Abe, 1974), (-)-xanthoxylol-4′- O - γ , γ -dimethylallyl ether ( 6 ) ( Bastos, Gottlieb, Sarti, & Filho, 1996 ), (+)-magnolin ( 7 ) ( Hua, Ah, Hee, Ryang, & Ho, 2004 ), (+)-eudesmin ( 8 ) ( Latip, Hartley, & Waterman, 1999 ), planispine A ( 9 ) ( Liu, Min, Huang, & Chen, 2019 ), (+)-piperitol ( 10 ) ( Terreaux, Maillard, Hostettmann, Lodi, & Hakizamungu, 2010 ), nodakenetin ( 11 ) ( Saeed & Sabir, 2008 ), bargapten ( 12 ) ( Li, 2009 ), imperatorin ( 13 ) ( Wang et al, 2008 ), demethylsuberosin ( 14 ) ( Masuda, Takasugi, & Anetai, 1998 ), pubinernoid A ( 15 ) ( Huang et al, 2006 ), linalyl- β -glucopyranoside ( 16 ) ( Omar, Noman, Mohamed, Altuntas, & Demirtas, 2018 ), (3S,5R,6S,7E)-5,6-epoxy-3-hydroxy-7-megastigmen-9-one ( 17 ) ( D”Abrosca et al, 2004 ), (3R,6R,7E)-3-hydroxy-4,7-megastigmadien-9-one ( 18 ) ( D”Abrosca et al, 2004 ), linalyl- O - β - d -glucoside ( 19 ) ( Sang, Min, Lee, Kim, & Kang, 2007 ), (-)epicatechin ( 20 ) ( Zhou & Yang, 2000 ), quercetin ( 21 ) ( Zhou & Yang, 2000 ), 4′- O -methyl catechin ( 22 ) ( Docampo-Palacios et al, 2020 ), 1 H -indole-3-carbaldehyde ( 23 ) ( Wang, Yang, Mei, & Yang, 2013 ), N 14 -formyldihydrorutaecarpine ( 24 ) ( Yang, Zhang, & Hu, 2008 ), 2,6,2′,6′-tetramethoxy-4,4′-bis(2,3-epoxy-1-hydroxypropyl)biphenyl ( 25 ) (Shiow-Hwa et al, 2001), cinnamic acid ( 26 ) ( Yang, Zhao, Ren, Mei, & Liang, 2003 ), loliolide ( 27 ) ( Willuhn & Westhaus, 1987 ), 4-hydroxy-3-methoxy-benzaldehyde ( 28 ) ( Ito et al, 2001 ), 2, 4-dihydroxy-6-methoxy acetophenone ( 29 ) ( Singh, Pathak, & Agrawal, 1997 ) by comparison with literatures.…”

(±)-Catechin—A Mass-Spectrometry-Based Exploration Coordination Complex Formation with FeII and FeIII

“…Nevertheless, the polyphenols' entrance into the brain tissues can be increased by pathological damage to the blood-brain barrier, which is associated with neurodegenerative disease [84]. Therefore, catechin derivatives with improved neuroprotection have recently been synthetized [85,86]. In recent years, the effects of polyphenols on gut-brain axis and gut microorganisms have been discussed [87,88].…”

Glucuronic acid metabolites of phenolic acids target AKT-PH domain to improve glucose metabolism

“…The secondary metabolites of quercetin can inhibit the activity of xanthine oxidoreductase, thereby reducing the plasma uric acid content in patients with hyperuricemia ( Tumova, Shi, Carr, & Williamson, 2021 ). Grape seed extract rich in flavonoids exerts an anti-Alzheimer's disease effect that is not directly related to the flavonoids in the diet, but related to their secondary metabolites, especially glucuronidated metabolites ( Docampo-Palacios et al, 2020 ).…”