Cytotoxicity of Natural Ginseng Glycosides and Semisynthetic Analogues

Atopkina, L. N.; Malinovskaya, G. V.; Elyakov, G. B.; Uvarova, N. I.; Woerdenbag, Herman J.; Koulman, Albert; Pras, Niesko; Potìer, Pierre

doi:10.1055/s-1999-13957

Cited by 49 publications

(35 citation statements)

References 7 publications

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“…It has been reported that ginsenosides are metabolized by intestinal bacterial and the intestinal bacterial metabolites were responsible for the main pharmacological activities of ginseng (12)(13)(14). However, the intestinal bacteria are liable to be influenced by a human's makeup and his dietary patterns.…”

Section: Introductionmentioning

confidence: 99%

pseudo-G-Rh2 induces mitochondrial-mediated apoptosis in SGC-7901 human gastric cancer cells

et al. 2011

Oncol Rep

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Abstract. This study was designed to investigate the effect of pseudo-G-Rh2, a novel metabolite of ginsenoside Rh2, on the apoptosis of SGC-7901 human gastric cancer cells. Pseudo-G-Rh2 demonstrated antitumor activity and significantly inhibited the proliferation of SGC-7901 cells in a concentration-dependent manner. After treatment with pseudo-G-Rh2, SGC-7901 cells showed typical apoptotic morphological features, such as chromatin condensation and DNA fragmentation. Pseudo-G-Rh2 could induce mitochondrial membrane potential loss, which led to the release of cytochrome c (Cyt c), Smac/Diablo and apoptosis-inducing factor (AIF) to the cell cytoplasm. Furthermore, pseudo-G-Rh2 exposure not only decreased the expression of the Bcl-2 protein but also increased the expression of the Bax protein and the activities of caspase-9 and caspase-3 in SGC-7901 cells. These results demonstrated that pseudo-G-Rh2 inhibited the proliferation of SGC-7901 cells by initiating apoptosis. Pseudo-G-Rh2-induced apoptosis was associated with a drop in the mitochondrial transmembrane potential, down-regulation of Bcl-2, up-regulation of Bax and activation of caspase-9 and caspase-3.

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Section: Introductionmentioning

confidence: 99%

pseudo-G-Rh2 induces mitochondrial-mediated apoptosis in SGC-7901 human gastric cancer cells

et al. 2011

Oncol Rep

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“…We prepared semisynthetic glycosides of 20S-protopanaxadiol and their analogs by chemical transformation of betulafolientriol, a component of the extract of birch (Betula) leaves [11][12][13][14]. Then, they were tested biologically [15][16][17][18][19][20]. Unfortunately, compounds that could be used as starting materials for synthesizing 20S-protopanaxatriol glycosides were not found among the many dammarane triterpenoids isolated from Betula leaves [21].…”

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Synthesis of panaxatriol glucosides

Atopkina

Денисенко

2009

Chem Nat Compd

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Glycosylation of 3β,6α,12β-trihydroxy-20R,25-epoxydammarane (panaxatriol) and its and 3, were synthesized for the first time.Key words: dammarane triterpenoids, panaxatriol, glycosylation, Panax ginseng C. A. Meyer, panaxatriol 3-O-β-Dglucopyranoside, panaxatriol 6-O-β-D-glucopryanoside, panaxatriol 12-O-β-D-glucopyranoside.Glycosides of dammarane triterpenoids are components of ginseng (Panax ginseng C. A. Meyer) extract and have for many years drawn attention due to the breadth and variety of their physiological activity [1][2][3][4][5][6][7][8]. Although the biological properties of ginseng extract have been studied and active components have been found, the mechanism of action of these compounds is still unknown and the structure-activity relationships have not been established. Observed differences in the properties of ginseng glycosides are often linked to the structuer of their aglycons. For example, the mechanisms of cytotoxicity for B16 melanoma cells differ greatly for ginsenosides Rh2 and Rh1, which have a single glucose on C-3 and C-6 but different aglycons [9, 10].One of the approaches to studying the structure-activity relationship is to synthesize compounds that are identical to the natural ones and those related to them for subsequent study of their properties using biological tests. Dammarane glycosides from P. ginseng are divided into two groups depending on the aglycon structure. These are glycosides of 20S-protopanaxadiol and those of 20S-protopanaxatriol, which differs from the former by having an additional hydroxyl on C-6. We prepared semisynthetic glycosides of 20S-protopanaxadiol and their analogs by chemical transformation of betulafolientriol, a component of the extract of birch (Betula) leaves [11][12][13][14]. Then, they were tested biologically [15][16][17][18][19][20]. Unfortunately, compounds that could be used as starting materials for synthesizing 20S-protopanaxatriol glycosides were not found among the many dammarane triterpenoids isolated from Betula leaves [21]. The most suitable and relatively available compound for evaluating the reactivity of the C-6 hydroxyl of dammarane triterpenoids for glycosylation compared to the C-3 and C-12 hydroxyls was 3β,6α,12β-trihydroxy-20R,25-epoxydammarane (panaxatriol, 1), one of the acid-hydrolysis products of the total glycoside fraction from P. ginseng root [22]. O Br OAc AcO AcO AcOCH 2 5 1: R 1 = R 2 = R 3 = H; 2: R 1 = R 2 = Ac, R 3 = H; 3: R 1 = Ac, R 2 = R 3 = H; 4: R 1 = R 3 = H, R 2 = Ac 6: R 1 = GlcAc 4 , R 2 = R 3 = H; 7: R 1 = R 2 = H, R 3 = GlcAc 4 ; 8: R 1 = R 2 = Ac, R 3 = GlcAc 4 9: R 1 = Ac, R 2 = GlcAc 4 , R 3 = H; 10: R 1 = Ac, R 2 = H, R 3 = GlcAc 4 ; 11: R 1 = GlcAc 4 , R 2 = Ac, R 3 = H 12: R 1 = H, R 2 = Ac, R 3 = GlcAc 4 ; 13: R 1 = Glc, R 2 = R 3 = H; 14: R 1 = R 2 = H, R 3 = Glc 15: R 1 = R 2 = Ac, R 3 = Glc; 16: R 1 = Ac, R 2 = Glc, R 3 = H; 17: R 1 = Ac, R 2 = H, R 3 = Glc 18: R 1 = Glc, R 2 = Ac, R 3 = H; 19: R 1 = H, R 2 = Ac, R 3 = Glc; 20: R 1 = R 3 = H, R 2 = Glc

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“…Ginseng glycosides are transformed by intestinal microflora in the gastro-intestinal tract into compounds with new biological properties. In the last few years, the properties and mechanism of action of one of the main metabolites of ginseng glycosides, 20S-protopanaxadiol 20-O-β-D-glucopyranoside (1) (compound K), have been studied more frequently [1][2][3][4][5][6][7][8][9][10][11][12][13]. Glucoside 1 inhibits the growth of tumor cells and induces their apoptosis [3,9,10], decreases the toxicity of antitumor preparations [4], possesses antimetastatic and immunomodulating activity [2,11], and exhibits antiallergic [12] and anti-inflammatory [13] properties.…”

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Synthesis of 20S-protopanaxadiol 20-O-β-D-glucopyranoside, a metabolite of Panax ginseng glycosides, and compounds related to it

Atopkina

Денисенко

2006

Chem Nat Compd

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Extract of Panax ginseng C. A. Meyer root, which is constantly attracting attention to itself owing to the breadth and variety of its biological activity, contains triterpene glycosides, which have been the subject of numerous investigations. Ginseng glycosides are transformed by intestinal microflora in the gastro-intestinal tract into compounds with new biological properties. In the last few years, the properties and mechanism of action of one of the main metabolites of ginseng glycosides, 20S-protopanaxadiol 20-O-β-D-glucopyranoside (1) (compound K), have been studied more frequently [1][2][3][4][5][6][7][8][9][10][11][12][13]. Glucoside 1 inhibits the growth of tumor cells and induces their apoptosis [3,9,10], decreases the toxicity of antitumor preparations [4], possesses antimetastatic and immunomodulating activity [2,11], and exhibits antiallergic [12] and anti-inflammatory [13] properties. In most of these investigations, 1 was prepared by treating ginseng extract or the enriched glycoside fraction with enzymes, bacteria, or intestinal microflora followed by chromatographic separation of the products of enzymatic hydrolysis.We previously prepared 1 as one of the condensation products of 20S-protopanaxadiol (dammar-24-en-3β,12β,20S-triol) (2) with 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosylbromide (α-acetobromoglucose) (3) under Koenig-Knorr reaction conditions [14,15]. Because all three hydroxyls of 3 were glycosylated, the main drawback was the lack of regioselectivity, which led to the formation of a complicated and difficultly separated mixture of mono-and diglucosides. Regioselective glycosylation of the 3,12-diacetate of 20S-protopanaxadiol (4) with one free hydroxyl on C-20 was unsuccessful [14], apparently because the 20-OH was sterically shielded by the 12β-OAc group.The present article is a continuation of investigations on the synthesis of glycosides based on tetracyclic dammarane triterpenoids. The goal was to develop a preparative semi-synthetic method for preparing 20S-protopanaxadiol 20-O-β-Dglucopyranoside (1).An attempt to synthesize 1 through regio-and stereoselective glycosylation of the tertiary hydroxyl on C-20 of 20S-hydroxydammar-24-en-3,12-dione (5) with subsequent reduction of both ketones on C-3 and C-12 into the glycosylation product (6) did not give the desired result. Reaction of 5 with 3 in the presence of Ag 2 O and 4Å molecular sieves in dichloroethane gave the tetraacetate of the diketone 20-O-β-D-glucopyranoside (6) (47% yield), reduction of which with NaBH 4 in isopropanol selectively reduced only one ketone on C-3 and formed the tetraacetate of 3β,20S-dihydroxydammar-24-en-12-one 20-O-β-D-glucopyranoside (7).

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Cytotoxicity of Natural Ginseng Glycosides and Semisynthetic Analogues

Cited by 49 publications

References 7 publications

pseudo-G-Rh2 induces mitochondrial-mediated apoptosis in SGC-7901 human gastric cancer cells

pseudo-G-Rh2 induces mitochondrial-mediated apoptosis in SGC-7901 human gastric cancer cells

Synthesis of panaxatriol glucosides

Synthesis of 20S-protopanaxadiol 20-O-β-D-glucopyranoside, a metabolite of Panax ginseng glycosides, and compounds related to it

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