ギンセノシドrh2とその誘導体は何ですか?

Ginseng (Panax ginseng C。 A. Meyer, Araliaceae) is のtraditional precious medicinal herb でChina. It has the effects のreplenishing vital energy, tonifying the spleen とbenefiting the lungs, generating body fluid, calming the mind and improving intelligence. The maでactive ingredient でginseng is ginsenoside, which can be divided into protopanaxadiol (PPD), protopanaxatriol (PPT) and oleanane (OA) types according to the aglycone. The ratios of PPD/PPT in the ginseng head, ginseng skin, ginseng leaves, ginseng root, and ginseng beard are 2.5, 1.9, 0.9, 1.2, and 3.8, respectively [1].

The content of ginsenosides of the PPD type is higher than that of the PPT type. For example, ginsenosides Rb1, Rb2, Rc, and Rd are the main ingredients in white ginseng, while ginsenosideRh2is a unique ingredient in red ginseng and is almost absent in white ginseng. In 1983, Japanese scholar Isao Kitagawa isolated ginsenoside Rh2from red ginseng, with a yield of only 0.001%. Nowadays, ginsenoside Rh2 is produced in kilogram quantities. “Jinxing Capsules”, produced by Zhejiang Yaxing Co., Ltd., is already on the marketas a health product. Ginsenoside Rh2has a wide range of pharmacological activities, such as anti-tumor, immune enhancement, anti-allergy, anti-inflammatory, hypoxia tolerance and obesity inhibition. This article reviews the relevant research on ginsenoside Rh2 at home and abroad.

Ⅰ。ギンセノシドrh2とその誘導体の構造

ギンセノシドrh2とその誘導体の構造を図1と表1に示す。

Ⅱ。ギンセノシドrh2およびその誘導体の調製方法

工業的な準備はginsenoside Rh2 has always been the focus of research by scholars at home and abroad, mainly focusing on the use of chemical and biotransformation methods to achieve the preparation of ginsenoside Rh2. The possible routes ためthe preparation of ginsenoside Rh2 are shown in Figure 2.

1. ギンセノシドrh2の調製法

(1)酸加水分解法。

The acid hydrolysis method is simple to operate and not affected by external environmental factors. However, the reaction products are complex and a large amount of waste acid is produced. The natural ginsenoside diol type saponin group C20 position configuration is mainly S configuration. When using acid hydrolysis to hydrolyze diol type saponin to prepare ginsenoside Rh2, the sugar group at the C20 position is first removed, and then a configuration change at the C20 position occurs, generating a mixture of two isomers, with the R configuration being the main one. Ginsenoside Rh2 is converted from ginsenoside Rg3 by acid degradation. The optimal degradation conditions are: 60% acetic acid, 55 °C for 1 h. The total content of ginsenoside Rg3 and Rh2 in the degradation product is 106.7 mg·g-1, and the yield is 71% [8]. The main products were ginsenoside Rg3 and 20(R) -Rh2 [2].

Yu Zhibo et アル[3] hydrolyzed American ginseng stem and leaf diol-type saponins and determined that the optimal conditions for preparing 20(R)-Rh2 were 80°C, 50% H2SO4 (5% by volume of ethanol), and degradation for 4 h. Zhang Lanlan et al. [9] applied for a patent for a ginseng saponin Rh2 extract in 2009, and the preparation method is as follows: step 1, the medicinal materials containing ginseng saponin components are extracted with water, the extract is passed through a macroporous adsorption resin column, eluted with ethanol, the eluate is collected, concentrated to dryness, to obtain the total saponin; step 2, dissolve the total saponin obtained in step 1 in an acid solution and react; after the reaction is complete, adjust the pH to neutral and collect the precipitate; step 3, perform reverse-phase silica gel column chromatography on the precipitate, elute with acetonitrile-water mixture, collect the fraction rich in ginsenoside Rh2, and concentrated to obtain the product.

(2)アルカリ加水分解法。

Alkali hydrolysis is simple to operate, and the product is relatively simple, but the hydrolysis conditions are harsh, the reaction equipment requirements are high, and a large amount of waste alkali is easily produced. When using the alkali hydrolysis method to prepare ginsenoside Rh2, the sugar group at the C20 position is first removed, and there is no conformational change at the C20 position. The alkali hydrolysis method can be used to prepare 20(S)-Rh2. The main products are 20(S)-Rh2 and PPD [2]. 20(S)-protoginseng diol-type saponin 8.0 g was dissolved in 30 mL of water, and 20 mL of saturated NaOH aqueous solution was added. The mixture was refluxed in a boiling water bath for 6 h, cooled, transferred to a separating funnel, and extracted with n-butanol four times. The n-butanol layer was concentrated, calculated that the conversion rate of 20(S) - Rh2 was 9.64% [10]. Li Xuwen [11] determined that the degradation conditions for the preparation of 20 (S) - Rh2 were: a mass ratio of NaOH to ginseng leaf total saponin of 1.6:1 (w/w), glycerol to ginseng leaf total saponin mass ratio of 15.0:1 (v/w), and 220 ℃ for 40 min, the conversion rate of 55.64%.

(3)微生物の形質転換法。

The microbial transformation method is dominant in the industrial preparation of ginsenoside Rh2 due to its many advantages, such as low cost and high conversion rate. To prepare ginsenoside Rh2 using the microbial transformation method, ginsenoside diol-type saponins are generally first converted into ginsenoside F2 or ginsenoside Rg3, and then into ginsenoside Rh2. Myrothecium verru- caria, isolated from the soil of ginseng in Changbai Mountain, can convert ginsenoside Rg3 to ginsenoside Rh2 and the diol-type saponin PPD[12]. Fusarium proliferatum ECU2042, isolated from soil, can convert ginsenoside Rg3 to ginsenoside Rh2 under the conditions of 50 °C and 50 mL NaAC/HAC (pH 5.0) for 24 h, with a conversion rate of up to 60% [13]. Zang Yunxia et al. [14] first hydrolyzed the ginseng extract with 1 mol·L-1 HCl, and then used the ginseng extract hydrolyzed by extended Aspergillus fermentation acid, resulting in the conversion of some ginsenosides to ginsenoside Rh2.

tong xinら[15]は、活性化乳酸菌delbrueckii subspを摂取した。菌媒体夫人に接种追加ginsenosides発酵37件°C ~ 39°C 240に248 h。発酵出汁を集め■サポニンglycosidase体と反応88℃时~ 92℃を240 ~ 360 h。反応解決策を集め、フィルタリングされ、ろ過液を溶出しあるエタノール勾配大和macroporous吸着树脂を使用。この流れを集めてギンセノシドrh2を得た。この特許取得済み製剤は高い変換率を有し、使用することができますギンセノシドrh2の大規模調製。呂国中らは2011年に、菌類の「シリンドロカルポンジジミウム」の使用と、その「シリンドロカルポンジジミウム」を使用して、「シリンドロカルポンジジミウム」を高麗人参病原性菌「シリンドロカルポンジジミウム」の調製に使用し、「シリンドロカルポンジジミウム」は、「シリンドロカルポンジジミウム」を使用して、「シリンドロカルポンジジミウム」をギンセノシドrb1とrdをギンセノシドrh2に変換する能力を持っている。ギンセノシドrb1またはrdを含むpda培地に接種し、25°cで5 - 7日間培養する。あるいは、液体発酵培地に株を接種し、28°cで5-7日間培養する微生物発酵変換法を用いることもできる。酵素溶液を収集し、ギンセノシドrb1またはrdと混合し、混合物を40°cで24時間反応させる。発酵生成物rh2の純度は85%以上です。

(4)酵素変換法。

Ginsenoside Rh2 is prepared in a targeted manner by using enzymes to selectively act on specific glycosidic bonds of ginsenosides. Ginsenoside α-arabinopyranosidase extracted from fresh ginseng roots can convert ginsenoside Rg3 to ginsenoside Rh2. The reaction conditions are as follows: Substrate concentration 10 mg·mL-1, pH 5.0, reaction at 55°C for 24 h, conversion rate up to 60% [17]. A new β-glycosidase purified from Fusarium proliferatum ECU204 can convert ginsenoside Rg3 to ginsenoside Rh2 [18]. Song Zhaohui et al. [19] applied for a patent in 2009 for a ginseng saponin Rh2 extract and a preparation method—extract medicinal materials containing ginseng saponins with water, allow the extract to settle, collect the supernatant, concentrate it to dryness, to obtain total saponins; dissolve the total saponins in a buffer solution with a pH of about 5, add β-glucosidase to react, collect the precipitate; dissolve the precipitate in ethanol, perform silica gel column chromatography, collect the fraction rich in ginsenoside Rh2, and concentrate to obtain. This laboratory has also made important progress in the preparation of ginsenoside Rh2 using industrial enzyme conversion with ginsenoside diol as a substrate.

(5)化学合成法。

Ginsenoside Rh2 can also be synthesized be synthesized chemically. Hui Yongzheng et al. [20] first selectively protected protopanaxadiol to obtain mono-substituted protopanaxadiol, and then subjected the mono-substituted protopanaxadiol to a glycosidation reaction with a glucose donor under the catalysis of a Lewis acid, and then removed the protective group to obtain 20(S)-Rh2 after separation and purification. This method has mild reaction conditions, low cost, high stereoselectivity of the reaction product, high yield and high purity. The invention is suitable for industrial large-scale production.

Ⅲ。ギンセノシドrh2誘導体の調製方法

後structural modification, ginsenoside Rh2 has enhanced water solubility and can be used as a prodrug to enter the body, delay the metabolic process of the drug in the body, and enhance its anti-cancer activity. Liu Jihua et al. [5] carried out a synthetic reaction of 20(S)-Rh2 with Boc-glycine to obtain five monomeric compounds; 20(S)-Rh2 reacted with Boc-alanine, Boc-arginine (Tos), Boc-lysine (Z), Boc-serine, and acetylproline, each resulting in a monomer compound; and the synthesis with acetylphenylalanine resulted in two monomer compounds. Wang Lu et al. [6] used the chlorosulfonic acid-pyridine method in combination with research on the modification of ginsenoside Rb1 by sulfation. The H on the different -OH positions on the Rh2 molecule was replaced with -SO3Na to obtain a pair of isomers. One isomer has the H on the C12 -OH position replaced, and the other has the H on the -OH position on the glc -C6 position replaced. which are abbreviated as S-Rh2 -1 and S-Rh2 -2, respectively. Wei et al. [7] dissolved ginsenoside Rh2 in chloroform, slowly added octyl chloroformate and Et3N, and reacted at room temperature for 15 min to obtain the ester D-Rh2.

Ⅳ。ギンセノシドrh2とその誘導体の薬理学的活性

Ginsenoside Rh2 includes two configurations, 20(S) and 20(R), while derivatives of ginsenoside Rh2 include sulfates, amino acid derivatives, esters, etc. The structures of ginsenoside Rh2 and its derivatives are different, and their pharmacological activities also differ greatly.

1. 薬理活性20(s)ギンセノシドrh2

大量のliterature 研究have shown that ginsenoside diol type 20(S)-Rg3 and the aglycone 20(S)-PPD have a strong inhibitory effect on tumor cell proliferation. Compared with the former two, 20(S)-Rh2 has stronger activity in inhibiting glioma cells A172 and T98G, breast cancer cells MCF7 and MDA-MB-468, and lung cancer cells H838, etc., its activity is stronger; while in inhibiting prostate cancer cells LNCaP and PC3, pancreatic cancer cells HPAC and Panc-1, lung cancer cells A549 and H358, etc., its activity is weaker than 20(S)-PPD [21].

20 (s)- rh2はcaco-2およびht-29細胞の成長を阻害する。20 (S) -Rh2会场内の48時間HT-29やCaco-2細胞する行为抑制濃度(IC50)が19.68との混血26.79μg・mL-1。作用機序は、20 (s) - rh2は、g0 / g1期およびg2 / m期におけるht-29細胞の割合を有意に減少させ、s期細胞の割合を増加させることである[22]。

2.20(r)ギンセノシドrh2薬理活性

20 (R) -Rh2 plays an important role in inhibiting papilloma and melanoma. Tao Lihua et al. [23,24] found that 20(R)-Rh2 has a significant inhibitory effect on mouse skin papilloma, B16 melanoma and B16-BL6 melanoma metastasis. The mechanism by which it 抑制malignant tumor metastasis may be related to its ability to reduce the invasiveness of cancer cells. Some studies have shown that after cancer cells form, they preferentially metastasize to the bone, and use cytokines in the bone to stimulate osteoclasts, thereby promoting cancer cell growth. Liu et al. [25] studied the in 体外inhibitory effect of 20(S)-Rh2 and 20(R)-Rh2 on osteoclast RAW264, found that only 20 (R) - Rh2 has the activity of inhibiting osteoclastogenesis, indirectly indicating that 20 (R) - Rh2 has the effect of inhibiting tumor cells.

Ⅴ。20 (s)/20 (r)ギンセノシドrh2の薬理学的活性の比較

Studies have shown that the anti-tumor activity of ginsenoside Rh2その形状と密接に関係しています20(r)- rh2および20(s)- rh2の同用量は、ヒト肺腺がん細胞a549に対して使用された。その結果、20(r)- rh2と20(s)- rh2はともにa549細胞のアポトーシスを促進し、a549細胞の増殖を用量依存的に阻害した。阻害率はそれぞれ28.5%と33.6%、ic50はそれぞれ33.4と28.5 mg・l-1であった。tip 20(r)- rh2と比較して、20(s)- rh2はa549細胞の阻害活性が強い[26]。前立腺がん細胞の増殖抑制(lncap、pc3、du145)に関する研究では、ic50が20(s)- rh2が最も低く、20(r / s)- rh2が2番目に低く、20(r)- rh2がic50が最も高かった。tungらは、ギンセノシドrh2によるヒト白血病hl-60細胞の阻害を研究したところ、20 (s) - rh2の方が20 (r) - rh2よりも活性が高いことを発見した[27]。ginsenoside rh2の研究で&#a-2780、hct-8、smmc-7721、pc-3mの細胞株を39;s阻害した結果、20(s)- rh2のic50は20(r)- rh2の約2倍小さいことが示された[28]。これらの結果は、ギンセノシドrh2の20位構造がその抗がん活性と密接に関連しており、20(s)- rh2が20(r)- rh2よりも強力であることを示している。

Ⅵ。ギンセノシドrh2誘導体の薬理活性

After being derivatized, ginsenoside Rh2 can significantly improve its water solubility and has immunostimulatory and antitumor activities. Zhu Wei et al. [29] found that Rh2 sulfates S-Rh2-1 and S-Rh2-2 can significantly inhibit ConA-induced proliferation of mouse splenic lymphocytes when the dosage is lower than that of Rh2, suggesting that Rh2 derivatives have enhanced immunological activity. Wei et al. [7] found that Rh2 esterified with D-Rh2 is significantly less toxic to the liver cell line QSG-7701 in vitro than Rh2, but both have a stronger inhibitory effect on the H22 liver cancer solid tumor in vivo, and the activity of the two is comparable, suggesting that Rh2 esterified with D-Rh2 is a more suitable anti-tumor candidate compound than Rh2.

Ⅶ。ギンセノシドrh2の薬物動態研究

guら[30]はそれを発見したbioavailability of ginsenoside Rh2 in rats and Beagle dogs after oral administration was 5% and 16%, respectively, indicating that the bioavailability of ginsenoside Rh2 varies in different species. Xie Haitang et al. [31] found that the bioavailability of ginsenoside Rh2 in male and female dogs was 17.6% and 24.8%, respectively, after ginsenoside Rh2 was administered to dogs by gavage, indicating that there are also differences in the bioavailability of ginsenoside Rh2 between the sexes. Gu et al. [30] administered ginseng saponin Rh2 to rats by gavage to study its tissue distribution, and the results showed that ginseng saponin Rh2 was mainly distributed in the liver and gastrointestinal tissues. Gu et al. [32] studied the absorption kinetics of 20(R)-Rh2 in different intestinal segments of rats and found that the absorption of 20(R)-Rh2 in the jejunum was the highest, and the absorption rate in the duodenum was the fastest.

Similar to other glycoside components, ginsenoside Rh2 is easily metabolized by intestinal flora after oral administration to produce corresponding aglycones. After ginseng saponin Rh2 was administered to rats by gavage, three metabolites of ginseng saponin Rh2, the de-glycosylated product m1, and the oxidation products m2 and m3, were detected in their feces, and a small amount of ginseng saponin Rh2 was also present in the feces. Note: Under the action of intestinal flora, ginsenoside Rh2 may undergo de-glycosylation and oxidation reactions [33].

Studies have shown that 20(S)-Rh2, when combined with digoxin and fexofenadine, can significantly alter the oral pharmacokinetic behavior of digoxin and fexofenadine [34]. Rats were pre-gavaged with 20(S)-Rh2, and 2 h later, digoxin and fexofenadine, which are P-glycoprotein (P-gp) substrates, were administered separately by gavage. The results showed that the AUC (area under the drug-time curve) of digoxin increased by 1.66 times, Cmax increased by 1.51 times, and the AUC of felodipine increased by 2.62 times, Cmax increased by 3.46 times. Isolated experiments showed that 20(S)-Rh2 can concentration-dependently increase the transport of digoxin A → B and reduce the transport of B → A, decreasing the efflux ratio of digoxin from 6.7 to 1.3. Its inhibitory effect is equivalent to that of the classic P-gp inhibitor verapamil. In addition, 20 (S) -Rh2 can concentration-dependently increase the uptake of rhodamine 123 by Caco-2 cells. It is suggested that 20 (S) -Rh2 is an effective non-competitive P-gp inhibitor.

Ⅷ。展望

Ginsenoside Rh2 その誘導体は薬理活性がよく、国内外の学者たちの注目を集めている。低コスト、高収率など多くの利点があり、ギンセノシドrh2の調製において重要な役割を果たしています。これらの研究に基づいて、ギンセノシドrh2の調製を目的とした様々なグリコシダーゼを有する遺伝子組付け細菌を構築することは、今後の研究の方向性の一つである。同時に、化学的および生物学的変換法を組み合わせてギンセノシドrh2およびその誘導体を調製し、それらの構造活性相関を詳細に研究することは、革新的な医薬品研究に使用するための創薬リードを発見する上で大きな意義があります。

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