- Structure-based design of glycyrrhetinic acid derivatives as potent anti-sepsis agents targeting high-mobility group box-1
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Novel Glycyrrhetinic Acid (GA) derivatives with fused heterocycles on A ring were structure-based designed and synthesized. Their potential anti-inflammatory effects were investigated by a classical LPS stimulated macrophage model. Surface plasmon resonance (SPR) was used to verify the binding of GA analogues with HMGB1. A preliminary structure–activity relationship was summarized and an analogue GA-60 with ortho-methoxybenzyl pyrozole showed stronger anti-inflammatory effect and higher affinity for HMGB1 with a Kd value of 12.5 μM. In addition, this compound exhibited excellent inhibitory functions on NO (96%), TNF-α (94%), and IL-6 (100%), by interfering with phosphorylation of p38, ERK, JNK MAPKs, as well as that of NF-κB p65 and IKKα/β. Moreover, GA-60 extended the survival of either the classic CLP-induced or LPS-induced sepsis mouse models. Molecular modeling predictions further supported these findings, clearly indicating that inhibiting HMGB1 release, using fused heterocyclic GA derivatives, is a promising strategy for treatment of sepsis.
- Wang, Yuanyuan,Yu, Zongmin,Yuan, Hu,Chen, Hao,Xie, Ning,Wang, Zhibin,Sun, Qingyan,Zhang, Weidong
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- Synthesis and inhibition of α-glucosidase of methyl glycyrrhetinate glycosides
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The synthesis of the methyl glycyrrhetinate glycosides and inhibition of α-glucosidase were studied. The carboxyl group of glycyrrhetinic acid was methylated, and glucose and galactose were introduced into the hydroxyl group to obtain compounds 7 and 12.
- Zhang, Wei,Wang, He-Ying,Wang, Huai-Xu,Zhu, Zhen-Yuan
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supporting information
p. 1874 - 1880
(2019/07/22)
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- Preparation method of 18 beta-methyl glycyrrhetinate
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The invention provides a preparation method of 18 beta-methyl glycyrrhetinate, which comprises the following steps: taking 18 beta-glycyrrhetinic acid and trimethylsilyl diazomethane as raw materials, and reacting to prepare the 18 beta-methyl glycyrrhetinate. According to the invention, 18 beta-glycyrrhetinic acid is used as a starting material and is subjected to one-step methyl esterification reaction with trimethylsilyl diazomethane to obtain 18 beta-methyl glycyrrhetinate, the synthesis process is simple, the synthesis process conditions are mild, the yield is up to 99.2% or above, the product quality is good, and the content is greater than 99.5%. Besides, through selection of a plurality of parameters such as the solvent, the reaction time and the material dosage, the yield and the purity of the reaction are further improved, and a basis is provided for industrial production.
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Paragraph 0024; 0030-0063
(2021/11/27)
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- Quaternary ammonium glycyrrhetinic acid cationic surfactant as well as preparation method and application thereof (by machine translation)
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The invention discloses a quaternary ammonium glycyrrhetinic acid cationic surfactant and a preparation method and application. thereof, and the critical micelle concentration of the surfactant at room temperature is 5 × 10. - 4 mol/L, Can descend the surface tension from 72mN/m to 47mN/m. and, the surfactant has better regulation and control effect on the bouncing behavior of the liquid drop on the hydrophobic solid surface, and the surfactant concentration on the surface of the blade such as dive, PTFE can be 5 × 10 higher. - 4 At mol/L, can obviously inhibit the liquid drop bouncing, and realize better spreading. and, the quaternary ammonium glycyrrhetinic acid cationic surfactant in the invention can extend to various crop blades, such as wheat, rice, corn, cabbage and other blades, have great application prospects, in the field of agricultural industry. (by machine translation)
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Paragraph 0041; 0043; 0044
(2020/05/01)
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- Synthesis and anti-hepaticfibrosis of glycyrrhetinic acid derivatives with inhibiting COX-2
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Many tests have shown cyclooxygenase-2 (COX-2) was closely related to the activation of hepatic stellate cells (HSCs), which further promoting the onset and development of hepatic fibrosis. According to these research findings, a series of glycyrrhetinic acid derivatives were designed and synthesized. Meanwhile, their anti-hepaticfibrotic activities were evaluated in vitro and in vivo. Firstly, in the tests of the cell models, all the compounds displayed anti-proliferative effect on the HSC-T6 activated by (transforming growth factor beta) TGF-β1 (10 ng/mL). Among them, compounds 2 and 16 exhibited a stronger activity than the others, and their IC50 values were 17.6 μM and 30.3 μM, respectively; both of them were low toxicity to normal HSC-T6 cells and WI38 cells, and they inhibited the activated HSC-T6 cells proliferation by promoting apoptosis and resting them at the G0/G1 phase. Secondly, compounds 2 and 16 displayed strong inhibitory effect on activation of HSCs; they not only inhibited the expression of α-SMA and Col1 in the activated HSC-T6 cells, but also decreased the levels of COX-2, TGF-β1 and (reactive oxygen species) ROS in a concentration-dependent manner; they down-regulated the levels of three biomarkers in the process of test, but this decrease did not change linearly with the action time of compound. Thirdly, for the rats which induced with (carbon tetrachloride) CCl4, the symptoms of liver fibrosis in rats were significantly alleviated after successive administration the tested compound for 14d; the α-SMA level in liver tissue decreased in a concentration dependent manner; and the liver cell necrosis and the fat collagen fiber decreased significantly compared with the positive control group; furthermore, inflammatory infiltration was significantly lower than that of the control. This suggests the compounds possibly are candidates for hepatic fibrosis with promising application in clinic.
- Bai, Zhongjie,He, Dian,Mohammed, Eyad Abdulwhab Hamoud,Wang, Yanni,Wang, Zhen,Zhang, Qiuping,Zhao, Quanyi
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- C3 and C20 diesterified glycyrrhetinic acid derivative, and preparation method and application thereof
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The invention provides a C3 and C20 diesterified glycyrrhetinic acid derivative having a structure represented by formula I shown in the description, or a pharmaceutically acceptable salt, a solvate,an optical isomer or a polymorph thereof. Experimental results show that the C3 and C20 diesterified glycyrrhetinic acid derivative has a very good bacteriostatic effect on Staphylococcus aureus, caninhibit Staphylococcus aureus ATCC 6538, Staphylococcus aureus ATCC 12228 and Staphylococcus aureus ATCC 29213, and provides a new choice for anti-infective drugs for Staphylococcus aureus.
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Paragraph 0064-0066; 0091
(2020/02/29)
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- Pentacyclic triterpenoid glycyrrhetinic acid derivative as well as preparation method and application thereof
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The invention discloses a pentacyclic triterpenoid glycyrrhetinic acid derivative which has a structure as shown in a general formula 1 or a formula 7 in the specification, wherein each substituent isdefined in detail in the specification. The invention also discloses application of the pentacyclic triterpenoid glycyrrhetinic acid derivative in preparation of anti-HCV drugs. Huh7 cytotoxic activity results show that the pentacyclic triterpenoid glycyrrhetinic acid derivative is low in cytotoxicity and has research value. In-vitro anti-HCVcc result shows that glycyrrhetinic acid has relativelyweak anti-HCVcc activity, but the pentacyclic triterpenoid glycyrrhetinic acid derivative has relatively good anti-HCV activity.
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Paragraph 0046; 0054; 0055
(2020/05/01)
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- Preparation method of glycyrrhetinic acid glucoside and application of glycyrrhetinic acid glucoside in sweetening agents
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The invention relates to a synthetic route of glycyrrhetinic acid glucoside and application of glycyrrhetinic acid glucoside in sweetening agents, and belongs to the field of synthesis of novel sweetening agents. The novel sweetening agent with higher swe
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Paragraph 0006; 0015-0017; 0025-0027
(2020/07/29)
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- Synthesis and antitumor effects of novel 18β-glycyrrhetinic acid derivatives featuring an exocyclic α,β-unsaturated carbonyl moiety in ring A
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A series of novel 18β-glycyrrhetinic acid (GA) derivatives featuring an exocyclic α,β-unsaturated carbonyl moiety in ring A were synthesized and evaluated for their antitumor activities. Compounds 5c and 5l showed stronger cytotoxicity than other compounds and reported GA analogue CDODA-Me (methyl 2-cyano-3,11-dioxo-18β-olean-1,12-dien-30-oate). 5c and 5l induced apoptosis in cancer cells accompanying with c-Flip reduction and Noxa induction, associated with decreased HDAC3 expression and increased acetylation of H3. 5l displayed better stability properties than 5c and CDODA-Me in microsomes and plasma, 5l also showed favorable pharmacokinetic profiles and inhibited tumor growth in mice. Compound 5l represents a new type of GA derivatives with improved antitumor activity.
- Huang, Min,Gong, Ping,Wang, Yuetong,Xie, Xiaorui,Ma, Zhuangshi,Xu, Qihao,Liu, Dan,Jing, Yongkui,Zhao, Linxiang
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- Application of acetyl glycyrrhetinic acid methyl ester in preparation of medicine for treating viral hepatitis B
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The invention relates to application of acetyl glycyrrhetinic acid methyl ester in preparation of a medicine for treating viral hepatitis B. Specifically, the invention provides an application of a compound shown as a formula (1), namely 3 beta-acetoxy-11-carbonyl oleanane-12-ene-30-carboxylic acid methyl ester, in preparation of a medicine for preventing and treating hepatitis B virus infection diseases. The compound shown in the formula (1) has remarkable activity of inhibiting HBeAg secreted by HepG2.2. 15 cells; under the concentration of 100 micrograms per milliliter, the intensity of inhibiting HBeAg secretion is 51.4% and is 3.78 times that of a positive control drug alpha-interferon (10000 units per milliliter) and 4.94 times that of lamivudine (100 micrograms per milliliter) respectively; under the concentration, the inhibition ratio of the lamivudine to HBV-DNA replication is 94.6%, and the inhibition strength (the inhibition ratio of 3-TC with the concentration of 100 micrograms per milliliter to HBV-DNA is 88.4%) of the lamivudine is higher than that of lamivudine with the same concentration and is 3.1 times that of high-concentration alpha-interferon (10000 units per milliliter). Therefore, the acetyl glycyrrhetinic acid methyl ester can be expected to be used for preparing non-nucleoside medicines for treating hepatitis B virus infection diseases; specifically, the compound can be used for preparing an HBV-DNA inhibitor and an HBeAg inhibitor, and the preparation method of the compound is simple in step, low in cost, wide in raw material source and easy for industrial production.
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Paragraph 0025; 0028-0031
(2020/11/25)
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- Derivatization, molecular docking and in vitro acetylcholinesterase inhibitory activity of glycyrrhizin as a selective anti-Alzheimer agent
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Acetylcholinesterase inhibitors (AChE-Is) increase both level and duration of action of acetylcholine (ACh); thus, alleviate symptoms of Alzheimer’s disease (AD). Glycyrrhizin, is the main active compound in liquorice root. Its aglycone, glycyrrhetinic acid, has shown several beneficial pharmacological activities. This study reports the synthesis and screening of a series of glycyrrhetinic acid analogs as AChE-Is. Fourteen derivatives were prepared, of which five derivatives are recorded as new viz., 3-phenyl-carbamoyl-18β-glycyrrhetinic acid (J9), 3-acetyl-18β-glycyrrhetinic-30-anilinamide (J10), 3-acetyl-18β-glycyrrhetinic-30-ethanolamide (J11), 3-acetyl-18β-glycyrrhetinic-30-n-butylamide (J12) and 18β-glycyrrhetinic acid-30-prenyl ester (J14), in addition to nine known derivatives (J1-J8 & J13). Compounds J12, J11, J0 and J3 showed remarkable AChE-I activity with IC50 values of 3.43, 5.39, 6.27 and 8.68?μM, respectively. These results are in full agreement with the docking study. The active compounds were non-cytotoxic to normal cells (WI-38).
- Abdel Bar, Fatma M.,Elimam, Diaaeldin M.,Mira, Amira S.,El-Senduny, Fardous F.,Badria, Farid A.
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p. 2591 - 2599
(2018/04/20)
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- Synthesis and antiproliferative activity of novel heterocyclic glycyrrhetinic acid derivatives
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A new series of glycyrrhetinic acid derivatives has been synthesized via the introduction of different heterocyclic rings conjugated with an α,β-unsaturated ketone in its ring A. These new compounds were screened for their antiproliferative activity in a panel of nine human cancer cell lines. Compound 10 was the most active derivative, with an IC50 of 1.1 μM on Jurkat cells, which is 96-fold more potent than that of glycyrrhetinic acid, and was 4-fold more selective toward that cancer cell line. Further biological studies performed in Jurkat cells showed that compound 10 is a potent inducer of apoptosis that activates both the intrinsic and extrinsic pathways.
- Alho, Daniela P.S.,Salvador, Jorge A.R.,Cascante, Marta,Marin, Silvia
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- Synthesis and antiproliferative activity of novel A-ring cleaved glycyrrhetinic acid derivatives
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A series of new glycyrrhetinic acid derivatives was synthesized via the opening of its ring A along with the coupling of an amino acid. The antiproliferative activity of the derivatives was evaluated against a panel of nine human cancer cell lines. Compound 17 was the most active compound, with an IC50 of 6.1 μM on Jurkat cells, which is 17-fold more potent than that of glycyrrhetinic acid, and was up to 10 times more selective toward that cancer cell line. Further biological investigation in Jurkat cells showed that the antiproliferative activity of compound 17 was due to cell cycle arrest at the S phase and induction of apoptosis.
- Alho, Daniela P.S.,Salvador, Jorge A.R.,Cascante, Marta,Marin, Silvia
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- Glycyrrhetinic acid type derivative as well as preparation method and application thereof
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The invention relates to a glycyrrhetinic acid type derivative as well as a preparation method and application thereof and belongs to the technical field of organic synthesis. The novel glycyrrhetinicacid type derivative has a molecular formula shown in t
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Paragraph 0042; 0049-0050
(2019/12/25)
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- Modification, Antitumor Activity, and Targeted PPARγStudy of 18β-Glycyrrhetinic Acid, an Important Active Ingredient of Licorice
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Licorice is a traditional Chinese medicine, which is often used as sweetener and cosmetic ingredients in food and pharmaceutical industries. Among them, glycyrrhetic acid is one of the most important agents. Studies have shown that glycyrrhetic acid exhibited antitumor activities as PPARγagonist. However, the limited number of PPARγglycyrrhetinic agonists and their high toxicity greatly limit the design based on the structure. Therefore, clarifying the binding mode between PPARγand small molecules, we focused on the introduction of a natural active piperazine skeleton in the position of glycyrrhetinic acid C-3. According to the Combination Principle and the Structure-Based Drug Design, 19 glycyrrhetic acid derivatives were designed and synthesized as potential PPARγagonists. Compounds 4c and 4q were screened as high-efficiency and low-toxicity lead compounds.
- Liu, Han-Yu,Lv, Cheng-Zhi,Qin, Jie,Sun, Juan,Wu, Yuan-Feng
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-
- Photoinduced Deoxygenative Borylations of Aliphatic Alcohols
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A photochemical method for converting aliphatic alcohols into boronic esters is described. Preactivation of the alcohol as a 2-iodophenyl-thionocarbonate enables a novel Barton–McCombie-type radical deoxygenation that proceeds efficiently with visible light irradiation and without the requirement for a photocatalyst, a radical initiator, or tin or silicon hydrides. The resultant alkyl radical is intercepted by bis(catecholato)diboron, furnishing boronic esters from a diverse range of structurally complex alcohols.
- Wu, Jingjing,B?r, Robin M.,Guo, Lin,Noble, Adam,Aggarwal, Varinder K.
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supporting information
p. 18830 - 18834
(2019/11/22)
-
- METHOD FOR MODIFYING T CELL POPULATION
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Provided are: a compound represented by formula (I); a retinoid metabolic pathway inhibitor comprising the same; an agent for increasing the ratio of memory T cells; a prophylactic and/or therapeutic agent for cancer or an infectious disease; a cancer immunotherapeutic adjuvant; an immunopotentiator; and a method for preparing a T cell population wherein the ratio of memory T cells is increased, said method comprising using the compound of formula (I).
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- Iridium-catalysed highly selective reduction-elimination of steroidal 4-en-3-ones to 3,5-dienes in water
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Steroidal 3,5-diene is an important structural motif in steroid drugs. In this report, an iridium-catalyzed reduction-elimination of readily available steroidal 4-en-3-ones is realized to prepare steroidal 3,5-dienes. At a low catalyst loading (S/C = 200), heating 4-en-3-ones in a water-mixed organic solvent with formic acid without inert atmosphere protection afforded the desired 3,5-dienes in moderate to excellent yields. In a gram-scale preparation, recrystallization is used instead of column chromatography to purify products. Excellent functionality tolerance and regioselectivity are featured. Structural moieties such as alkanols (primary, secondary and tertiary), esters (except for formate), tolylates, and ketones (endocyclic or exocyclic) are not affected. Surprisingly, the reduction-elimination only takes place at A-ring 4-en-3-ones. In addition, bicyclic 4-en-3-ones are also viable substrates. Synthetic applications of steroidal 3,5-dienes are demonstrated. Our method can also lead to steroidal 3,5-dienes-3-d (>99% d-incorporation) when DCO2D and D2O are used together.
- Li, Jide,Tang, Weiping,Ren, Demin,Xu, Jiaxi,Yang, Zhanhui
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supporting information
p. 2088 - 2094
(2019/04/29)
-
- Targeting mitochondria: Esters of rhodamine B with triterpenoids are mitocanic triggers of apoptosis
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Triterpenoic acids, ursolic acid (1), oleanolic acid (2), glycyrrhetinic acid (3) and betulinic acid (4) were converted into their corresponding methyl 5–8 and benzyl esters 9–12 or benzyl amides 21–24. These derivatives served as starting materials for the synthesis of pink colored rhodamine B derivatives 25–36 which were screened for cytotoxicity in colorimetric SRB assays. All of the compounds were cytotoxic for a variety of human tumor cell lines. The activity of the benzyl ester derivatives 29–32 was lower than the cytotoxicity of the methyl esters 25–28. The benzyl amides 33–36 were the most cytotoxic compounds of this series. The most potential compound was a glycyrrhetinic acid rhodamine B benzyl amide 35. This compound showed activity against the different cancer cell lines in a two-digit to low three-digit nano-molar range. Staining experiments combined with fluorescence microscopy showed that this compound triggered apoptosis in A2780 ovarian carcinoma cells and acted as a mitocan.
- Wolfram, Ratna Kancana,Heller, Lucie,Csuk, René
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supporting information
p. 21 - 30
(2018/04/26)
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- Sensitized Aliphatic Fluorination Directed by Terpenoidal Enones: A "visible Light" Approach
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In our continued effort to address the challenges of selective sp3 C-H fluorination on complex molecules, we report a sensitized aliphatic fluorination directed by terpenoidal enones using catalytic benzil and visible light (white LEDs). This sensitized approach is mild, simple to set up, and an economical alternative to our previous protocol based on direct excitation using UV light in a specialized apparatus. Additionally, the amenability of this protocol to photochemical flow conditions and preliminary evidence for electron-transfer processes are highlighted.
- Bume, Desta Doro,Harry, Stefan Andrew,Pitts, Cody Ross,Lectka, Thomas
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p. 1565 - 1575
(2018/02/09)
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- Glycyrrhetinic acid derivative with piperazine structure and preparation method and application thereof
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The invention discloses a glycyrrhetinic acid derivative with piperazine structure and a preparation method and application thereof. The glycyrrhetinic acid derivative has a structural shown as in formula (I). The invention also discloses the preparation method and application of the glycyrrhetinic acid derivative. The glycyrrhetinic acid derivative can significantly inhibit cancer cells; the materials used are cheap, simple and easily accessible; the reaction steps are few; the yield is high; the glycyrrhetinic acid derivative is suitable for industrial production and is a pilot drug having apromising prospect.
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Paragraph 0031; 0033; 0037; 0038
(2018/10/19)
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- 2-substituted-18beta-glycyrrhetic acid derivative and application thereof
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The invention belongs to the technical field of medicine, and specifically relates to a 18beta-glycyrrhetic acid derivative and an opticalisomeride and a salt acceptable pharmaceutically thereof. According to a preparation method of the derivative, a medicine composition with the derivative as an active component is used for preparing drugs treating and/or preventing cancers. The derivative as shown in a general formula I, the opticalisomeride and the salt acceptable pharmaceutically have the following structure, wherein each variable is as shown in the claims and the description. The formulaI is shown in the description.
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Paragraph 0166; 0167-0169
(2018/11/22)
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- Synthesis and anti-influenza virus evaluation of triterpene-sialic acid conjugates
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We are interested in new non-natural glycosides with sialic acid conjugates and their biological activities. We report the synthesis of eleven non-natural occurring glycosides, which are triterpene (glycyrrhetinic acid and its derivatives)-sialic acid conjugates, and their inhibitory activities against influenza virus sialidases and influenza virus multiplication in MDCK host cells. Deoxoglycyrrhetol-sialic acid conjugates (6d and 6e) and oleanolic acid-sialic acid conjugates (7d and 7e) showed strong inhibitory activities against three subtypes of influenza virus sialidases. These four compounds (6d, 6e, 7d and 7e) showed clear inhibition to influenza virus multiplication but not to MDCK host cell survival.
- Tsuji, Mitsuru,Sriwilaijaroen, Nongluk,Inoue, Hideo,Miki, Kazuhiko,Kinoshita, Kaoru,Koyama, Kiyotaka,Furuhata, Kimio,Suzuki, Yasuo,Takahashi, Kunio
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-
- Synthesis of 2-Cyanoethoxy and 2-(1H-Tetrazol-5-yl)ethoxy Derivatives of Glycyrrhetic Acid Methyl Ester
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Cyanoethylation of natural glycyrrhetic acid methyl ester gave the corresponding 3β-O-(2-cyanoethyl) derivative which was treated with sodium azide to obtain a novel tetrazolyl derivative of biologically active triterpenoid, methyl 3β-[2-(1H-tetrazol-5-yl)ethoxy]-11-oxoolean-12-en-30-oate.
- Zorina,Polozova,Marchenko,Selivanov,Trifonov
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p. 1868 - 1870
(2019/03/26)
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- Multiple Enone-Directed Reactivity Modes Lead to the Selective Photochemical Fluorination of Polycyclic Terpenoid Derivatives
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In the realm of aliphatic fluorination, the problem of reactivity has been very successfully addressed in recent years. In contrast, the associated problem of selectivity, that is, directing fluorination to specific sites in complex molecules, remains a great, fundamental challenge. In this report, we show that the enone functional group, upon photoexcitation, provides a solution. Based solely on orientation of the oxygen atom, site-selective photochemical fluorination is achieved on steroids and bioactive polycycles with up to 65 different sp3 C-H bonds. We have also found that γ-, β-, homoallylic, and allylic fluorination are all possible and predictable through the theoretical modes reported herein. Lastly, we present a preliminary mechanistic hypothesis characterized by intramolecular hydrogen atom transfer, radical fluorination, and ultimate restoration of the enone. In all, these results provide a leap forward in the design of selective fluorination of complex substrates that should be relevant to drug discovery, where fluorine plays a prominent role.
- Pitts, Cody Ross,Bume, Desta Doro,Harry, Stefan Andrew,Siegler, Maxime A.,Lectka, Thomas
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supporting information
p. 2208 - 2211
(2017/02/23)
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- Glycyrrhetinic acid derivative synthesis and use thereof
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The invention designs and synthetizes a lead compound by using a glycyrrhetinic acid derivative as a carrier and being connected with norcantharidin and a derivative thereof through ester bonds, the obtained lead compound expects to have the advantages of having liver targeting action, prolonging action time, reducing toxic and side effects and improving the curative effect of resisting liver cancer, and a model compound is provided for the research of a liver targeting medicine for the liver cancer. Firstly, two positions of C11 and C30 in glycyrrhetinic acid molecules are reduced and synthetized respectively, methyl ester is chemically modified into glycyrrhetinic acid (GA) and 18 alpha-glycyrrhetinic acid as well as a derivative thereof, the glycyrrhetinic acid (GA) and 18 alpha-glycyrrhetinic acid as well as the derivative thereof are used as framework molecules, through a series of reactions, the framework molecules and the norcantharidin (NCTD) as well as a derivative thereof are condensed to form ester as a prodrug, a cell activity screening test is performed on 5 object compounds, 13 object compounds in 3 series are synthetized, and structural characterization is performed on a carbon spectrum, a hydrogen spectrum and a mass spectrum; the influence of different concentrations of 5 object compounds on HepG2 cell proliferation of the liver cancer is inspected by a method, results show that inhibitory action presents time-dose dependence, and the suppression ratio of 14 mu g/mL is the highest.
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Paragraph 0021; 0036; 0037
(2017/08/24)
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- Conjugates of 18β-glycyrrhetinic acid derivatives with 3-(1H-benzo[d]imidazol-2-yl)propanoic acid as Pin1 inhibitors displaying anti-prostate cancer ability
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Twenty-six conjugates of 18β-glycyrrhetinic acid derivatives with 3-(1H-benzo[d]imidazol-2-yl)propanoic acid were designed and synthesized as Pin1 inhibitors. Most of these semi-synthetic compounds showed improved Pin1 inhibitory activity and anti-proliferative effects against prostate cancer cells as compared to 3-(1H-benzo[d]imidazol-2-yl)propanoic acid and GA. Compounds 10a and 12i were the most potent to inhibit growth of prostate cancer PC-3 with GI50 values of 7.80 μM and 3.52 μM, respectively. The enzyme inhibition ratio of nine compounds at 10 μM was over 90%. Structure-activity relationships indicated that both appropriate structure at ring C of GA and suitable length of linker between GA skeleton and benzimidazole moiety had significant impact on improving activity. Western blot assay revealed that 10a decreased the level of cell cycle regulating protein cyclin D1. Thus, these compounds might represent a novel anti-proliferative agent working through Pin1 inhibition.
- Li, Kun,Ma, Tianyi,Cai, Jingjing,Huang, Min,Guo, Hongye,Zhou, Di,Luan, Shenglin,Yang, Jinyu,Liu, Dan,Jing, Yongkui,Zhao, Linxiang
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p. 5441 - 5451
(2017/10/06)
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- Scalable and sustainable electrochemical allylic C-H oxidation
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New methods and strategies for the direct functionalization of C-H bonds are beginning to reshape the field of retrosynthetic analysis, affecting the synthesis of natural products, medicines and materials. The oxidation of allylic systems has played a prominent role in this context as possibly the most widely applied C-H functionalization, owing to the utility of enones and allylic alcohols as versatile intermediates, and their prevalence in natural and unnatural materials. Allylic oxidations have featured in hundreds of syntheses, including some natural product syntheses regarded as € classics €. Despite many attempts to improve the efficiency and practicality of this transformation, the majority of conditions still use highly toxic reagents (based around toxic elements such as chromium or selenium) or expensive catalysts (such as palladium or rhodium). These requirements are problematic in industrial settings; currently, no scalable and sustainable solution to allylic oxidation exists. This oxidation strategy is therefore rarely used for large-scale synthetic applications, limiting the adoption of this retrosynthetic strategy by industrial scientists. Here we describe an electrochemical C-H oxidation strategy that exhibits broad substrate scope, operational simplicity and high chemoselectivity. It uses inexpensive and readily available materials, and represents a scalable allylic C-H oxidation (demonstrated on 100 grams), enabling the adoption of this C-H oxidation strategy in large-scale industrial settings without substantial environmental impact.
- Horn, Evan J.,Rosen, Brandon R.,Chen, Yong,Tang, Jiaze,Chen, Ke,Eastgate, Martin D.,Baran, Phil S.
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- Synthesis and Hypoglycemic Activity of 11-Deoxoglycyrrhetic Acid Derivatives
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New 2-hydroxy-1-en-3-ones were prepared by oxidation of 11-deoxoglycyrrhetic acid 3-oxo-derivatives and its 30-methyl ester by atmospheric oxygen in the presence of t-BuOK. 2-Hydroxy-3-oxo-18βH-olean-1,12-dien-30-oic acid at a dose of 50 mg/kg reduced the blood glucose concentration in the alloxan-induced rat diabetes mellitus model by 34% compared with the control after 120 min.
- Budaev,Mikhailova,Spirikhin,Makara,Zarudii,Baltina
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p. 441 - 444
(2016/07/26)
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- First Occurrence of a Furano-glycyrrhetinoate and Its Cytotoxicity
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(18α)-Glycyrrhetinic acid (4) was prepared from (18β)-glycyrrhetinic acid (1), and the cytotoxicity of some derivatives was investigated by photometric SRB assays employing several human tumor cell lines. In summary, (18β)-1 is slightly more cytotoxic than its (18α) epimer 4, but its cytotoxicity is negligible. Higher cytotoxicity was observed for the esters 2 and 5 and for the 3-O-acetylated esters 3 and 6. Cytotoxicity was improved dramatically when the hydroxyl group at position C-3 was replaced by an amino moiety. SeO2 oxidations gave access to a novel furano-glycyrrhetinoate 15. Interestingly, its seleno analog 16 is approximately five to six times less cytotoxic for the tumor cell lines tested, and tumor/non-tumor selectivity is lost upon replacement of the oxygen by a selenium substituent.
- Heller, Lucie,Sommerwerk, Sven,Tzsch?ckell, Felix,Wiemann, Jana,Schwarz, Stefan,Siewert, Bianka,Al-Harrasi, Ahmed,Csuk, René
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p. 889 - 896
(2015/12/24)
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- Design, synthesis, and biofunctional evaluation of novel pentacyclic triterpenes bearing O-[4-(1-piperazinyl)-4-oxo-butyryl moiety as antiproliferative agents
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A series of pentacyclic triterpenoids derivatives bearing O-[4-(1-piperazinyl)-4-oxo-butyryl moiety has been synthesized and investigated for their potential antiproliferative activities. Pentacyclic triterpenoids derivative compounds were synthesized by a four or six step synthetic procedure. The activity studies were evaluated using Cell Counting Kit-8 method, and Western blotting analysis on A549 cells, MCF-7 cells and Hela cells. Compounds methyl 3-O-[4-(1-piperazinyl)-4-oxo-butyryl]olean-12-ene-28-oate (OA-4) and compound 2-O-[4-(1-piperazinyl)-4-oxo-butyryl]-3,23-dihydroxyurs-12-ene-28-oate (AA-5) were found to be promising antiproliferative agents. These compounds show potentiality for further optimization as antitumor drugs.
- Zhao, Chun-Hui,Zhang, Cui-Li,Shi, Jin-Jie,Hou, Xi-Yan,Feng, Bin,Zhao, Long-Xuan
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supporting information
p. 4500 - 4504
(2015/10/12)
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- Synthesis of novel 2-cyano substituted glycyrrhetinic acid derivatives as inhibitors of cancer cells growth and NO production in LPS-activated J-774 cells
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Here we report the synthesis and biological activity of new semi-synthetic derivatives of naturally occurring glycyrrhetinic acid bearing a 2-cyano-3-oxo-1-en moiety in the A-ring and double bonds and carbonyl groups in the C, D and E rings. Bioassays using murine macrophage-like and tumor cells show that compound 4, which differs from Soloxolone methyl by the absence of a 9(11)-double bond in the C-ring, displays anti-inflammatory and inhibitory activities with respect to tumor cells with a high selectivity index value.
- Salomatina, Oksana V.,Markov, Andrey V.,Logashenko, Evgeniya B.,Korchagina, Dina V.,Zenkova, Marina A.,Salakhutdinov, Nariman F.,Vlassov, Valentin V.,Tolstikov, Genrikh A.
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p. 585 - 593
(2014/01/17)
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- Inhibition of human enterovirus 71 replication by pentacyclic triterpenes and their novel synthetic derivatives
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A large number of bioactive pentacyclic triterpenoids have been shown to have multiple biological activities. This study was conducted to evaluate the inhibitory activities of 6 newly synthesized and novel pentacyclic triterpenoids against enterovirus 71 (EV71). The parent compound, ursolic acid (UA), showed the greatest inhibitory activity against EV71, while oleanolic acid (OA), asiatic acid (AA), and synthetic derivatives of 18-β-glycyrrhetinic acid (GA) and OA also exhibited inhibitory effects, although to lesser extents. The results suggest these compounds show potential for further optimization as antiviral candidates for treatment of EV71 infections.
- Zhao, Chun-Hui,Xu, Jie,Zhang, Ying-Qiu,Zhao, Long-Xuan,Feng, Bin
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p. 764 - 771
(2016/10/06)
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- Sulfamates of methyl triterpenoates are effective and competitive inhibitors of carbonic anhydrase II
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Carbonic anhydrase II, belonging to one of the most important enzyme groups of the human body, is a well-studied isozyme from the family of the carbonic anhydrases. Since it is involved in several physiological processes, it has been a pharmaceutical target for many years. In this study we synthesized a number of sulfamates derived from pentacyclic methyl triterpenoates, and we demonstrate their potential as carbonic anhydrase II inhibitors using the well-established photometric 4-nitrophenyl acetate assay. Inhibition constants, as an indicator of their inhibition strength, were in the micromolar range; one compound (10, methyl (3β) 3-(aminosulfonyloxy)-oleanoate) showed a Ki value as low as 0.3 μM. This Ki value is comparable to that of acetazolamide which is a potent carbonic anhydrase inhibitor and a drug for the treatment of glaucoma.
- Schwarz, Stefan,Sommerwerk, Sven,Lucas, Susana D.,Heller, Lucie,Csuk, René
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- Synthesis of methyl 2-cyano-3,12-dioxo-18β-olean-1,9(11)-dien-30-oate analogues to determine the active groups for inhibiting cell growth and inducing apoptosis in leukemia cells
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Fourteen of the methyl 2-cyano-3,12-dioxo-18β-olean-1,9(11)-dien-30- oate (CDODO-Me-12, 10d) analogues with different structures of ring C were synthesized to determine the active groups for inhibiting cell growth and inducing apoptosis in human leukemia HL-60 cells. An unsaturated group in ring C was required to maintain the ability to inhibit cell growth and induce apoptosis. Compound 10e with 9(11),12-dien in ring C displayed comparable apoptosis induction ability to 10d associated with decreased levels of c-FLIP, but not Mcl-1 and XIAP. Compound 10e had decreased ability to deplete GSH compared to compound 10d. Compound 10e represents a new active compound acting through a different mechanism from that of compound 10d. This journal is the Partner Organisations 2014.
- Li, Xiaojing,Wang, Yuetong,Gao, Yuan,Li, Lei,Guo, Xin,Liu, Dan,Jing, Yongkui,Zhao, Linxiang
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p. 6706 - 6716
(2014/08/18)
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- GLYCYRRHETINIC ACID DERIVATIVES AND METHODS OF USE THEREOF
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The present application relates to: (a) compounds of Formula (I): and salts thereof, wherein Y and Z are as defined in the specification; (b) compositions comprising such compounds and salts; and (c) methods of use of such compounds, salts, and compositions, particularly use for the treatment and prevention of diseases such as those associated with oxidative stress and inflammation.
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Paragraph 0460
(2014/03/25)
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- Does one keto group matter? Structure-activity relationships of glycyrrhetinic acid derivatives modified at position C-11
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Several triterpenoic acids display a remarkable cytotoxicity on tumor cells. Glycyrrhetinic acid - the main content of the licorice root - possesses an apoptotic effect on tumor cells. Previous studies pointed out the presence of a keto group at position C-11 in glycyrrhetinic acid derivatives as the main reason for its apoptotic activity. Several pairs of derivatives were synthesized differing only at position C-11. These compounds were tested in a sulforhodamine B colorimetric assay for cytotoxicity screening on 12 tumor cell lines and mouse embryonic fibroblasts (NIH3T3). Our results show that there is no direct relation between the existence of the C-11 keto group and the apoptotic activity of the compounds. It remains disputable whether the C11 keto group in glycyrrhetinic acid derivatives is the main reason for their apoptotic effect. Copyright
- Csuk, Rene,Schwarz, Stefan,Kluge, Ralph,Stroehl, Dieter
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experimental part
p. 28 - 32
(2012/03/27)
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- Synthesis, biological evaluation and structure-activity relationships of glycyrrhetinic acid derivatives as novel anti-hepatitis B virus agents
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Fifty-seven derivatives of glycyrrhetinic acid (GA) were synthesized, and their anti-hepatitis B virus (HBV) activity was evaluated in HepG 2.2.15 cells. Among them, sixteen compounds showed greater anti-HBV activity than GA, especially, compounds 29, 32, 35, 41 exhibited significantly inhibitory activities against HBV DNA replication with IC50 values of 5.71, 5.36, 8.90 and 9.08 μM, respectively. The structure-activity relationships (SARs) of GA derivatives were discussed for exploring novel anti-HBV agents.
- Wang, Li-Jun,Geng, Chang-An,Ma, Yun-Bao,Huang, Xiao-Yan,Luo, Jie,Chen, Hao,Zhang, Xue-Mei,Chen, Ji-Jun
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supporting information; experimental part
p. 3473 - 3479
(2012/07/03)
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- Synthesis, characterization and in vitro evaluation of self-assembled poly(ethylene glycol)-glycyrrhetinic acid conjugates
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Glycyrrhetinic acid (GA) is a commonly used drug for the chemotherapy of Chronic Hepatitis B, allergic dermatitis, inflammation, etc. But some problems such as poor water-solubility, low bioavailability and short plasma halflife, have limited its use. In the present study, PEGylation derivatives of GA derivatives were synthesized and characterized by FTIR, NMR, transmission electron microscopy, particle size analysis, etc. The PEG-GA conjugates having a critical micelle concentration of 0.081-0.73 mg/mL were used to form nano-sized micelles, with mean diameters of 120.86 ± 31.74 nm. The physico-chemical properties of the PEG-GA conjugate were evaluated including stability, cellular toxicity, and drug release profile. All the conjugates synthesized showed good stabilities in acidic and neutral solutions, while the stability in alkaline solution and the enzymatic hydrolysis rate, were significantly affected by the linkage between the GA and PEG chain. The results demonstrate that, by PEGylation of GA derivatives, the greatly increased water solubility and desirable self-assembly abilities of PEG-GA were obtained. The novel conjugates have potential medical applications for intravenously delivery of insoluble drug delivery.
- He, Gu,He, Zhiyao,Zheng, Xi,Li, Junmin,Liu, Chi,Song, Xiangrong,Ouyang, Liang,Wu, Fengbo
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experimental part
p. 202 - 210
(2012/08/08)
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- Synthesis of fan-shaped C3 molecule with three glycyrrhetinic acid units and self-assembly properties
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A novel fan-shaped C3 molecule with three glycyrrhetinic acid units was synthesized via "click chemistry" in high yield and the self-assembly characteristics were studied in different mixed solvents.
- Hu, Jun,Yu, Libing,Zhang, Meng,Ju, Yong
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scheme or table
p. 1139 - 1142
(2012/04/23)
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- Synthesis and antitumor activity of ring A modified glycyrrhetinic acid derivatives
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Triterpenoic acids show many pharmacological effects, among them an antiinflammatory or an antitumor activity. One of these, glycyrrhetinic acid (1) is of interest because of its antitumor profile. Glycyrrhetinic acid is not only cytotoxic but also triggers apoptosis in various human tumor cell lines. To improve the cytotoxicity of parent 1 we set out to synthesize new derivatives of it - differing in structure and lipophilicity. These compounds were tested in a sulforhodamine B assay for cytotoxicity, and screened for their ability to induce apoptosis using an acridine orange/ethidium bromide assay and trypan blue staining. The most active compound, 34, a benzyl glycyrrhetinate holding an extra 3-N-(3-aminopropyl)glycyl substituent showed IC50 between 1.96 and 5.14 μm for five human cancer cell lines and triggers apoptosis in 80% of the cells.
- Csuk, René,Schwarz, Stefan,Siewert, Bianka,Kluge, Ralph,Str?hl, Dieter
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scheme or table
p. 5356 - 5369
(2012/01/19)
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- Synthesis and antitumour activity of glycyrrhetinic acid derivatives
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Glycyrrhetinic acid (GA) is one of many interesting triterpenoic acids showing anticancerogenic potential. GA is known to trigger apoptosis in tumour cell lines, although GA has a low cytotoxicity. In our study we were able to prepare derivatives of GA that show lowered the IC50 values as determined by a sulforhodamine B (SRB) assay using 15 different human tumour cell lines. Thus, combining an ester group combined with the presence of an amino acid moiety led to a ca. 60-fold improved antitumor activity. Experiments on mouse embryonic fibroblasts (NiH3T3) revealed that these compounds showed a better selectivity for tumour cells compared to the parent compound GA. An apoptotic effect of some of these compounds was determined using an acridine orange/ethidium bromide (AO/EB) test and DNA laddering experiments.
- Schwarz, Stefan,Csuk, René
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experimental part
p. 7458 - 7474
(2011/01/04)
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- Synthesis and biological activity of some antitumor active derivatives from glycyrrhetinic acid
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Aminoalkyl substituted derivatives were synthesized starting from glycyrrhetinic acid methyl ester and screened for antitumor activity in a panel of 15 human cancer cell lines by an SRB assay. The most compound 7 possesses an aminohexyl side chain, induces apoptosis and shows IC50 values of 0.6-3.0 μM.
- Csuk, René,Schwarz, Stefan,Kluge, Ralph,Str?hl, Dieter
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experimental part
p. 5718 - 5723
(2011/02/23)
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- Synthesis and binding ability of 1,2,3-triazole-based triterpenoid receptors for recognition of Hg2+ ion
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A novel type of receptors based on 1,2,3-triazole glycyrrhetinic acid derived from natural triterpenoid molecules has been synthesized via click chemistry and they showed high selectivity and affinity for Hg2+ ion by both the 1,2,3-triazole rin
- Hu, Jun,Zhang, Meng,Yu, Li B.,Ju, Yong
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scheme or table
p. 4342 - 4345
(2010/10/21)
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- Synthesis and anti-HIV activity of triterpene 3-o-galactopyranosides, analogs of glycyrrhizic acid
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A new method for synthesizing triterpene 3-O-galactosides, analogs of glycyrrhizic acid (GA) based on 18β- glycyrrhetic acid (GLA) methyl esters and 18,19-dehydro-GLA, using 2,3,4,6-tetra-O-acetyl-α-Dgalactopyranosyl bromide as the glycosyl donor, I-Br promoter, and 4-A molecular sieves was developed. The method could produce primarily 3-O-α-D- or β-D-galactopyranosides depending on the reaction conditions. The 3-O-α-D-galactopyranoside of GLA exhibited an index of selectivity (IS) 2.9 times greater than that of GA for inhibition of accumulation of virus-specific protein p24 of HIV-1. β-D-Galactopyranoside of GLA was more cytotoxic for MT-4 cells and exhibited weak anti-HIV-1 activity.
- Baltina Jr.,Baltina,Kondratenko,Plyasunova,Nepogodiev,Field
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experimental part
p. 576 - 582
(2010/12/25)
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- Synthesis and biological evaluation of furoxan-based nitric oxide-releasing derivatives of glycyrrhetinic acid as anti-hepatocellular carcinoma agents
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A series of novel furoxan-based nitric oxide (NO)-releasing derivatives of glycyrrhetinic acid (GA) were designed, synthesized, and evaluated for their in vitro cytotoxicity against human hepatocellular carcinoma (HCC) and non-tumor liver cells. Five furoxan/GA hybrids, 7b-d, 7f, and 7g, displayed potent cytotoxicity against HCC cells (IC50: 0.25-1.10 μM against BEL-7402 cells and 1.32-6.78 μM against HepG2 cells), but had a little effect on the growth of LO2 cells, indicating that these compounds had selective cytotoxicity against HCC cells. Furthermore, these compounds produced high concentrations of NO in HCC cells, but low in LO2 cells and treatment with hemoglobin partially reduced the cytotoxicity of the hybrid in HCC cells. Apparently, the high concentrations of NO produced by NO donor moieties and the bioactivity of GA synergistically contribute to the cytotoxicity, but the NO is a major player against HCC cells in vitro. Potentially, our findings may aid in the design of new chemotherapeutic reagents for the intervention of human HCC at clinic.
- Lai, Yisheng,Shen, Lihong,Zhang, Zhenzhen,Liu, Wenqing,Zhang, Yihua,Ji, Hui,Tian, Jide
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scheme or table
p. 6416 - 6420
(2010/11/18)
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- Development of glycyrrhetinic acid-modified stealth cationic liposomes for gene delivery
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The glycyrrhetinic acid-modified stealth cationic liposomes (GA-PEG-CLs) loaded with pDNA (GA-PEG-CLPs) were developed and found to transfect human hepatocellular carcinoma cell line HepG2 with high efficiency. GA-PEG-CLs were comprised of DOTAP, cholesterol (Chol) and glycyrrhetinic acid-polyethyleneglycol-cholesterol conjugate (GA-PEG-Chol). Agarose gel electrophoresis revealed that 5% GA-PEG-CLs constituted by DOTAP/Chol/GA-PEG-Chol at molar ratio of 50:45:5 could completely entrap pDNA at a lower liposomes/pDNA weight ratios of 4:1 (N/P ratio: 1.14). Compared to ordinary cationic liposomes (CLs), steric cationic liposomes (PEG-CLs) and 1% GA-PEG-CLs made from DOTAP/Chol/MPEG2000-Chol/GA-PEG-Chol at molar ratio of 50:45:4:1, 5% GA-PEG-CLs were found to possess the highest transfection efficiency as gene vectors in serum-free or serum-containing medium in PKCα over-expressed HepG2 cells but no significance difference in human embryonic kidney cell line HEK 293. Additionally, 5% GA-PEG-CLs have the lowest cytotoxicity on human normal hepatocyte cell line L02. The competitive inhibition experiments mediated by GA were carried out in HepG2 cells, which demonstrated that GA-PEG-CLs could deliver selectively pDNA to hepatoma cells by the targeting moiety GA. In conclusion, GA-PEG-CLs containing 5% GA-PEG-Chol might be one of the most potential gene vectors as hepatoma targeting therapy.
- He, Zhi Yao,Zheng, Xi,Wu, Xiao Hua,Song, Xiang Rong,He, Gu,Wu, Wen Fang,Yu, Shui,Mao, Sheng Jun,Wei, Yu Quan
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scheme or table
p. 147 - 154
(2011/12/03)
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- Synthesis of glycyrrhetinic acid derivatives for the treatment of metabolic diseases
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The effect of glycyrrhetinic acid (GA) and GA-derivatives towards 11β-hydroxysteroid dehydrogenase (11β-HSD) was investigated. Novel compounds with modifications at positions C-3, C-11 and C-29 of the GA skeleton were prepared. Single crystal X-ray diffraction data of selected substances are reported and discussed.
- Beseda, Igor,Czollner, Laszlo,Shah, Priti S.,Khunt, Rupesh,Gaware, Rawindra,Kosma, Paul,Stanetty, Christian,Ruiz-Ruiz, Maria Carmen del,Amer, Hassan,Mereiter, Kurt,Cunha, Thierry Da,Odermatt, Alex,Classen-Houben, Dirk,Jordis, Ulrich
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experimental part
p. 433 - 454
(2010/03/30)
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- Antitumoractive endoperoxides from triterpenes
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A series of triterpene endoperoxides was synthesized and screened for antitumor activity in a panel of 15 human cancer cell lines by a sulforhodamine-B (SRB) assay. The compounds induce apoptosis and show excellent antitumor activity.
- Niesen, Anja,Barthel, Alexander,Kluge, Ralph,Koewitzsch, Alexander,Stroehl, Dieter,Schwarz, Stefan,Csuk, Rene
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experimental part
p. 569 - 576
(2009/12/24)
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- Synthesis, anti-inflammatory, and antioxidant activities of 18β-glycyrrhetinic acid derivatives as chemical mediators and xanthine oxidase inhibitors
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Twenty 18β-glycyrrhetic acid (18β-GA) derivatives 2-21 including 13 new 18β-GA derivatives were synthesized and evaluated as anti-inflammatory and antioxidant agents. Compounds 7 and 20 with a 3,4-seco-structure and compound 6 with a lactone moiety showed potent inhibitory effect on superoxide anion generation in rat neutrophils response to fMLP/CB and PMA, respectively. Compound 6 with a lactone moiety revealed stronger inhibitory effect on XO activity than those of compounds 13 and 14 with a 3,4-seco-struture. Compound 14, a 30-isoproylcarbamoyl seco-compound exhibited potent inhibitory effect on NO accumulation and iNOS protein expression while compounds 3, 10, 13, 15, 17, and 21 revealed potent inhibitory effect on tumor necrosis factor-α (TNF-α) formation in RAW 264.7 cells in response to lipopolysaccharide (LPS). The cleavage of ring A of 3 attenuated the inhibitory effect on TNF-α formation in RAW 264.7 cells in response to LPS except for 17. The present results suggested these compounds were potential to be served as anti-inflammatory and antioxidant agents.
- Maitraie, Dravidum,Hung, Chi-Feng,Tu, Huang-Yao,Liou, Ya-Ting,Wei, Bai-Luh,Yang, Shyh-Chyun,Wang, Jih-Pyang,Lin, Chun-Nan
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experimental part
p. 2785 - 2792
(2009/08/15)
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