Ginsenoside Rh2와 그 파생물이란 무엇입니까?

Ginseng (Panax ginseng C다. A. Meyer, Araliaceae) is 한traditional precious medicinal herb 에서China. It has the effects 의replenishing vital energy, tonifying the spleen 그리고benefiting the lungs, generating body fluid, calming the mind and improving intelligence. The ma에서active ingredient 에서ginseng 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.

Ⅰ다.ginsenoside Rh2의 구조와 그 유도체

ginsenoside Rh2 및 그 유도체의 구조를 그림 1 및 표 1에 나타내었다.

Ⅱ다.ginsenoside Rh2 및 그 유도체의 제조 방법 (Preparation methods 을ginsenoside Rh2 and its derivatives

…의 산업적 준비ginsenoside 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 for the preparation of ginsenoside Rh2 are shown in Figure 2.

1. Ginsenoside Rh2 준비 방법

(1) 산가수분해법.

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 알다.[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) 알칼리 가수분해법.

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) 미생물 형질전환법.

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.

통신 등 15명은 활성화된 Lactobacillus delbrueckii subsp.bulgaricus와 MRS medium에 접종하고, ginsenosides를 첨가하고, 37°C 내지 39°C에서 240시간 내지 248시간 동안 발효시킨 발효 국물을 88℃~92℃에서 240~360시간 동안 saponin glycosidase와 반응시켜 반응 용액을 채취하고, 여과하고, 여과액을 대성 흡착수지를 통해 에탄올 배지로 용출하였다.flow fraction을 수집하여 ginsenoside Rh2를 얻었다.이 특허 받은 준비물은 전환율이 높고에 사용할 수 있습니다ginsenoside Rh2의 대규모 준비다.Lv 구오종 등 [16]은 진세노사이드 Rb1 및 Rd를 진세노사이드 Rh2로 전환하는 능력이 있는 진세노사이드 Rh2-a 인삼 병원성 곰팡이 진세노사이드 원통형 카폰디뮴 제조 및 이의 용도를 2011년 특허를 출원했다.곰팡이는 ginsenoside Rb1 또는 Rd를 함유한 PDA 매체에 접종하여 25 °C에서 5-7일간 배양한다.또는, 균주를 액상 발효 배지에 접종하여 5-7일 동안 28°C에서 배양하는 미생물 발효 전환 방법을 사용할 수 있다.효소용액을 채취하여 ginsenoside Rb1 또는 Rd와 혼합하고, 혼합물을 40°C에서 24시간 동안 반응시킨다. ginsenoside Rh2를 생산하기 위한 본 발명의 기술적 용액은 특이성이 높고, 단순하고 편리하며, 비용이 저렴하고 부산물이 적은 것이 특징이다.발효 생성물인 Rh2의 순도는 85% 이상이다.

(4) 효소전환법.

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) 화학합성방법.

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.

Ⅲ다.ginsenoside Rh2 유도체의 준비 방법

후structural 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.

Ⅳ다.ginsenoside Rh2 및 그 유도체의 약리학적 활동

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. 20(S) ginsenoside Rh2의 약리학적 활성

…의 다수literature 연구have 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)-Rh2는 Caco-2와 HT-29세포의 성장에 억제 효과가 있다.20 (S)-Rh2 후 48 시간 동안 HT-29와 Caco-2 세포에 작용 하여, 억제 절반 농도 (IC50) 19.68었고 26.79 μ g · mL-1, 각각이다.작용 기작은 20 (S)-Rh2는 G0/G1 상 및 G2/M 상에서 HT-29세포의 비율을 현저히 줄일 수 있고, S 상 세포의 비율을 증가시킬 수 있다 [22].

2.20(R) ginsenoside Rh2 약리학적 활성

20 (R)-Rh2에서 등장 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 억제malignant 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 체외inhibitory 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.

Ⅴ다.20 (S)/20 (R) ginsenoside Rh2의 약리학적 활성 비교

Studies have shown that the anti-tumor activity of ginsenoside Rh2의 구성과 밀접한 관련이 있습니다.사람의 폐 선암 세포인 A549에 동일한 용량의 20(R)-Rh2와 20(S)-Rh2를 사용하였다.그 결과, 20(R)-Rh2와 20(S)-Rh2 모두 A549세포의 사멸을 촉진하였으며, 둘다 A549세포의 증식을 용량의존적으로 억제하였으며, 각각 28.5%와 33.6%의 저해율을 보였고, IC50 값은 각각 33.4와 28.5 mg·L-1 이었다.Tip 20(R)-Rh2, 20(S)-Rh2와 비교하면 A549세포를 억제하는 활성이 더 강하다 [26].전립선암세포 (LNCaP, PC3, DU145)의 증식억제에 관한 연구에서 20(S)-Rh2의 IC50 값이 가장 낮았고, 20(R/S)-Rh2의 IC50 값이 두 번째로 낮았으며, 20(R)-Rh2의 IC50 값이 가장 높았다.Tung 등 (27)은 ginsenoside Rh2에 의한 인체 백혈병 HL-60세포의 억제를 연구하였을 때 20 (S)-Rh2가 20 (R)-Rh2보다 더 활발함을 발견하였다.ginsenoside Rh2&의 연구에서#39;s 가 서로 다른 세포주인 A-2780, HCT-8, SMMC-7721, PC-3M을 저해하는 결과 20(s)-Rh2의 IC50이 20(R)-Rh2의 IC50보다 2배 가까이 작은 것으로 나타났다 [28].이러한 결과는 ginsenoside Rh2의 20위치 구성이 항암활성과 밀접한 관련이 있으며, 20(S)-Rh2가 20(R)-Rh2보다 더 강력한 활성을 나타낸다는 것을 보여준다.

Ⅵ다.ginsenoside Rh2 유도체의 약리학적 활성

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.

Ⅶ다.ginsenoside Rh2의 약리연구

구 등 [30]은 다음과 같은 사실을 발견했다bioavailability 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.

Ⅷ다.전망

Ginsenoside Rh2 그리고 그 파생물은 좋은 약리학적 활성으로 인해 국내외 학자들의 관심을 끌고 있다.생물 변환 기술은 낮은 비용과 높은 수율과 같은 많은 장점을 가지고 있으며, ginsenoside Rh2의 준비에 중요한 역할을 합니다.이와 관련된 연구를 바탕으로 다양한 glycosidases로 변형된 박테리아를 구성하여 ginsenoside Rh2의 목표 제제를 달성하는 것이 향후 연구 방향 중 하나가 될 것이다.동시에 화학적 및 생물학적 형질전환 방법을 복합적으로 이용한 ginsenoside Rh2 및 그 유도체의 제조와 이들의 구조-활성 관계에 대한 심도 있는 연구는 혁신적인 약물 연구에 사용할 수 있는 약물 선도체의 발견에 매우 중요하다.

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[18] Su JH, 수 JH, 유 HL 등.소설의 속성 β-glucosidase에서 Fusarium proliferatum ECU204 변환 ginsenoside Rg3 Rh2로 변 했다.J Mol Catal B:Enzym, 2009, 57:278~283.

[19] 송자휘, 장랄란, 황지안 등.ginsenoside Rh2 추출물 및 동일한 제조 방법.CN 200910228463.2 [p] 2011-05-18 이승철.

[20]Hui YZ, Yang ZQ, Liu JY 등.20(S)-ginsenoside Rh2의 합성.CN 200410053269 [p] 2005-03-02 「 길림신문 」 기자

[21] Wang W, Zhao YQ, Rayburn ER 등이 있다.파낙스 인삼의 과실에서 분리한 천연물의 In vitro 항암 액티비티 및 구조-활성 관계.Cancer Chemother Pharmacol, 2007, 59:589-601.

[22] 리큐잉, 얀 루루, 마샤오후이 등 20명-Ginsenoside Rh2는 인간 대장암 세포의 증식과 주기에 영향을 미친다.한의학, 2011, 33:1874~1878.

[23] 타오리화, 가오펑, 푸자오디 등.20 (R)-ginsenoside Rh2의 DMBA/croton 오일 유발 마우스 피부 유두종에 대한 억제 효과에 관한 연구.Shi Zhen Guo Yi Guo Yao, 2006, 17:1950~1954.

[24] 도련화, 류홍옌, 한루이 20(R)-ginsenoside Rh2는 B16-BL6 흑색종 전이를 억제한다.Liaoning Journal of Traditional Chinese Medicine, 2006, 33:1505~1506.

[25] 류제이, 시오노 J, Shimizu K, et al. 20 (S)-가 아닌 20 (R)-ginsenoside Rh2는 세포 독성이 없는 선택적 골세포 발생 억제제입니다.Bioorg Med Chem Lett, 2009, 19:3320~3323.

[26] Zhang C, Yu H, Hou J. S-및 r 형 ginsenoside Rh2가 사람 폐선암 A549세포의 증식과 세포사멸에 미치는 영향.대한한의학회지 2011년, 36:1670~1674.

[27] Tung NH, Song GY, Minh CV 등이 있다.찐 산삼 잎 성분은 인체 백혈병 HL-60세포에 대한 세포 독성 효과를 강화합니다., Chem Pharm Bull, 2010년,58:1111~1115.

[28] Ma, C.J. 반합성 희귀 진세노사이드의 항암구조-활성 관계에 관한 연구.청도:중국과학원 해양연구소 박사학위 논문, 2005.

[29] 주위, 푸벤동, 왕루 등.sulfated 20의 효과 (S)-ginsenoside Rh2 IL-4과 IFN-γ에 마우스 비장 림프 구에 의해 분비 합니다.헤이룽장 축산업과 수의학 (과학기술판), 2011, 7:17~19.

[30] Gu Y, Wang GJ, Sun JG 외.인삼의 항암영양소인 ginsenoside Rh2의 쥐와 개의 약리작용 특성 (Pharmacokinetic characteristics of ginsenoside Rh2 in rats and dogs)Food Chem Toxicol, 2009, 47:2257-2268.

[31]시 HT, Wang GJ, Lv H 외.천연물로부터 새로운 항암 물질인 ginsenoside Rh2에 대한 HPLC-MS assay 개발 및 개에서의 약리학적 연구.Eur J Drug Metab Pharmacokinet, 2005, 30:63-67.

[32] 구 Y, 왕 G, 장 J 등 20 (R)-Ginsenoside Rh2장내 흡수 kinetics in rats.한국임상약리학회지 2009년, Chinese Journal of Clinical Pharmacology and Therapeutics, 1468-373.

[33] 그레나다 TX, 채 ZW, 웡 RN.S, 외. 에 대한 쥐 시료의 액체 크로마토그래피/질량 분석법 분석 in  생체 실험 신진대사  그리고 pharmacokinetic studies  of  ginsenoside  Rh2다. 빠 른  Commun 질량분석학 (Mass Spectrom), 2005, 19:3549~3554.

[34] 장 JW, 저 우 F, Wu  XL, et  al.  20 (S)-진세노사이드 Rh2   noncom-petitively inhibits  P-glycoprotein in  vitro   and  in  생체 실험:  a  사건 for  herb-drug 상호작용이다.마약 Metab Dispos, 2010,  38:2179~2187.