Gallotannins and Tannic Acid: First Chemical Syntheses and In Vitro Inhibitory Activity on Alzheimer’s Amyloid β‐Peptide Aggregation

Abstract

The screening of natural products in the search for new lead compounds against Alzheimers disease has unveiled several plant polyphenols that are capable of inhibiting the formation of toxic b-amyloid fibrils.G allic acid based gallotannins are among these polyphenols,but their antifibrillogenic activity has thus far been examined using "tannic acid", ac ommercial mixture of gallotannins and other galloylated glucopyranoses.T he first total syntheses of two true gallotannins,ahexagalloylglucopyranose and ad ecagalloylated compound whose structure is commonly used to depict "tannic acid", are nowd escribed. These depsidic gallotannins and simpler galloylated glucose derivatives all inhibit amyloid b-peptide (Ab)a ggregation in vitro,a nd monogalloylated a-glucogallin and an atural b-hexagalloylglucose are shown to be the strongest inhibitors.Abnormal amyloid b-peptide (Ab)accumulation and aggregation into toxic fibrils is one of the major processes occurring during the progression of Alzheimers disease (AD), which today affects approximately 36 million people worldwide. [1a, 2] Although the etiology of this severe neurodegenerative disorder,w hich causes dementia in the elderly,r emains unknown, [1b,2] ag lobal effort was initiated in the early 1990s to search for neuroprotective therapeutic agents with antifibrillogenic activity. [1c,d] In this context, natural-product screening programs were implemented with the aim of identifying molecules that are capable of preventing the aggregation and/or promoting the clearance of Ab. [1c,e] Afew recent investigations have focused on plant polyphenols, which are known for their antioxidant activity and their metal-chelation and protein-binding abilities,aset of properties that makes them potentially good candidates as multifunctional drugs for the treatment of AD and other fibrillogenic neurodegenerative disorders,s uch as Parkinsons and Huntingtons diseases. [1c,e,3] Curcuminoids,s uch as curcumin itself,stilbenoids,s uch as resveratrol, and flavonoids,s uch as myricetin and epigallocatechin gallate (EGCg), all belong to aselect group of plant polyphenols that have been identified as inhibitors of Ab aggregation, mainly in vitro. [1c, 4] Gallic acid based polyphenols,s uch as the gallotannins and ellagitannins (Scheme 1), [3a, 5, 6a,b] have surprisingly been mostly left aside in these investigations,likely because of the difficulties associated with accessing them in pure form.Concerning the gallotannins,tothe best of our knowledge, investigations have been limited to the evaluation of 1) their ultimate precursor,1 ,2,3,4,6-penta-O-galloyl-b-d-glucopyranose (b-PGG, b-3;Scheme 1), which was shown to inhibit Ab fibril formation and to destabilize pre-formed Ab fibrils in vitro and in vivo, [7a] and 2) commercial tannic acid (TA), which was reported to destabilize Ab fibrils in vitro. [7b] TA is the sole available standard that is commonly but inappropriately used to assess the (biological) properties of gallotannins. [8,9a] It is usually depicted as the meta-deps...

Metal-phenolic networks as a versatile platform to engineer nanomaterials and biointerfaces

“…Commercially available TA is in fact a mixture of gallotannins and other galloylated glucopyranoses extracted from plants, and the total synthesis of decagalloylglucose commonly used to represent TA (the chemical structure shown in Fig. 1), has just recently accomplished [91]. This total synthesis of the representative TA molecule should enable more detailed investigations into the stoichiometry of metal ions and gallol groups, which may assist with elucidation of the MPN structures.…”

Mitigating Alzheimer’s Disease with Natural Polyphenols: A Review

“…Gallotannins such as hexagalloylglucopyranose and galloylated glucose derivatives all inhibit A aggregation in vitro, and monogalloylated alpha-glucogallin and a natural beta-hexagalloylglucose are reported to be the strongest inhibitors [129]. However, the neuroprotective effects of gallic acid (GA) derivatives appear to be more dependent on their molecular polarities than on antioxidant activities in the human SH-SY5Y cell line [159].…”

“…Curcumin directly binds with small amyloid-species to inhibit aggregation and fibril formation in vitro and in vivo[99], and to destabilize preformed fibrils at concentrations between 0.1 M and 1.0 M[101,128]. As monitored by UV spectroscopy at 200nm, curcumin's inhibition of A $& fibrillization was 49 +/ 9%[129]. Molecular docking revealed curcumin's preferential interaction with the lateral oligomer region, near the 17-21 amino acid residues of A $% peptide[130].Under in vitro aggregating conditions, curcumin inhibited aggregation (IC50= 0.8 M), and disaggregated fibrillar A $% (IC50= 1.0 M)[99].…”

Anti-Oxidant Activity of Gallotannin-Enriched Extract of Galla Rhois Can Associate with the Protection of the Cognitive Impairment through the Regulation of BDNF Signaling Pathway and Neuronal Cell Function in the Scopolamine-Treated ICR Mice

“…Among the various antioxidants, tannin and tannin-related plant extracts have received great attention, since recent studies have demonstrated the tight correlation between antioxidant treatments and symptomatic relief of AD symptoms [6]. The aggregation and production of Aβ are significantly inhibited by exposure to gallotannin and tannic acid in in vitro studies and the PSAPP mouse model presenting AD-like pathology [7,8]. Moreover, similar inhibitory effects on Aβ plaque deposition and β-amyloid fibrils (fAβ) formation have been reported in APP/PS1 and PSAPP Tg mice treated with pomegranate polyphenols and tannic acid [9,10].…”