Dual action of acertannins as potential regulators of intracellular ceramide levels

Abstract

Derived from the genus maple (Acer), acertannins are a group of gallotannins which have a characteristic 1,5-anhydro-D-glucitol (1,5-AG) occupying the central core position in the tannic acid structure whose hydroxyl groups have one or more galloyl residues. We synthesized all ten naturallyoccurring acertannins and seven new acertannin derivatives from 1,5-AG. Side-by-side comparison revealed that 2,4,6-trigalloyl-1,5-AG (maplexine E : 21) and maplexine F (2,3,6-trigalloyl-1,5-AG : 22) were good inhibitors of ceramidase (CDase). In contrast, the core anhydrosugar 1,5-AG (12) itself and methoxygallate derivatives (23-25) did not show CDase inhibition. Metabolic labeling experiments using NBD-hexanoic acid revealed that 50 µM 6-galloyl-1,5-AG (Ginnalin B : 16), 2,6-digalloyl-1,5-AG (Ginnalin A : 19), and 4,6-digalloyl-1,5-AG (4) increased intracellular NBD-labeled ceramide, by 2.3, 2.2, and 2.1-fold, respectively. It is noteworthy that these acertannins (16, 19, and 4) promoted ceramide synthase 3 (CERS3) gene expression. Acertannins, therefore,represent a new class of potential intracellular ceramide regulators exhibiting both CDase inhibition and ceramide synthase promotion.

Synthesis and Comparative Structure–Activity Study of Carbohydrate-Based Phenolic Compounds as α-Glucosidase Inhibitors and Antioxidants

“…Recently, A. Kamori et al reported the synthesis of various natural and unnatural acertannin derivatives and evaluated their SAR against ceramidase and ceramide synthase enzymes [35]. In addition, we have also previously reported a facile method for the preparation of 1,5-anhydroalditol via treatment of per- O -TMS-glycopyranosyl iodide with LiBH 4 [41].…”

“…Firstly, 4,6- O -benzylidene-1,5-AG ( 1 ) [42] was protected with benzyl (Bn) group using BnBr and NaH to afford di-benzylated compound 2 [42] . However, reacting 1 in a 2-phase dichloromethane (DCM)/5% NaOH system with BnBr, NaI, and tetra- n -butylammonium hydrogen sulfate provided the 3-OH analog 3 [35] and the 2-OH analog 4 [35] as a mixture of products, which could be separated by column chromatography (C.C.) (Scheme 1) [43].…”

“…Compounds 2 – 4 were then deprotected with 80% acetic acid/H2normalO solution to give the corresponding diol analogs 5 – 7 [35,42]. Reduction of 1 , 3 , and 4 by BH 3 /THF and trimethylsilyl trifluoromethanesulfonate (TMSOTf) [44], and reduction of 2 by diisobutylaluminium hydride (DIBAL-H) [45] resulted in the formation of the 6-OH derivatives 8 – 11 [35,46,47]. Moreover, compounds 1 – 4 were treated with triethylsilane and trifluoroacetic acid (TFA) [48] to afford the 4-OH derivatives 12 – 15 [35,49].…”

“…Reduction of 1 , 3 , and 4 by BH 3 /THF and trimethylsilyl trifluoromethanesulfonate (TMSOTf) [44], and reduction of 2 by diisobutylaluminium hydride (DIBAL-H) [45] resulted in the formation of the 6-OH derivatives 8 – 11 [35,46,47]. Moreover, compounds 1 – 4 were treated with triethylsilane and trifluoroacetic acid (TFA) [48] to afford the 4-OH derivatives 12 – 15 [35,49]. Esterification of these -OH derivatives with Bn-protected gallic acid ( 16 ) [50] using N , N -dimethyl-4-aminopyridine (DMAP) and triethylamine (TEA), as well as 2-chloro-1-methylpyridinium iodide as the condensing reagent, provided 1,5-AG-based galloylated derivatives 17 – 30 .…”

“…These polyphenols were shown to exhibit different bioactivities such as α-glucosidase inhibition and antioxidant activity. It is noteworthy that different numbers, positions, and types of the phenol units on the 1,5-AG core display non-identical bioactivities [32,33,34,35,36].…”