- Synthesis and biological evaluation of pentacyclic triterpenoid derivatives as potential novel antibacterial agents
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A series of ursolic acid (UA), oleanolic acid (OA) and 18β-glycyrrhetinic acid (GA) derivatives were synthesized by introducing a range of substituted aromatic side-chains at the C-2 position after the hydroxyl group at C-3 position was oxidized. Their antibacterial activities were evaluated in vitro against a panel of four Staphylococcus spp. The results revealed that the introduction of aromatic side-chains at the C-2 position of GA led to the discovery of potent triterpenoid derivatives for inhibition of both drug sensitive and resistant S. aureus, while the other two series derivatives of UA and OA showed no significant antibacterial activity even at high concentrations. In particular, GA derivative 33 showed good potency against all four Staphylococcus spp. (MIC = 1.25–5 μmol/L) with acceptable pharmacokinetics properties and low cytotoxicity in vitro. Molecular docking was also performed using S. aureus DNA gyrase to rationalize the observed antibacterial activity. This series of GA derivatives has strong potential for the development of a new type of triterpenoid antibacterial agent.
- Wu, Panpan,Tu, Borong,Liang, Jinfeng,Guo, Shengzhu,Cao, Nana,Chen, Silin,Luo, Zhujun,Li, Jiahao,Zheng, Wende,Tang, Xiaowen,Li, Dongli,Xu, Xuetao,Liu, Wenfeng,Zheng, Xi,Sheng, Zhaojun,Roberts, Adam P.,Zhang, Kun,Hong, Weiqian David
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- Indole-and pyrazole-glycyrrhetinic acid derivatives as ptp1b inhibitors: Synthesis, in vitro and in silico studies
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Regulating insulin and leptin levels using a protein tyrosine phosphatase 1B (PTP1B) inhibitor is an attractive strategy to treat diabetes and obesity. Glycyrrhetinic acid (GA), a triter-penoid, may weakly inhibit this enzyme. Nonetheless, semisynthetic derivatives of GA have not been developed as PTP1B inhibitors to date. Herein we describe the synthesis and evaluation of two series of indole-and N-phenylpyrazole-GA derivatives (4a–f and 5a–f). We measured their inhibitory activity and enzyme kinetics against PTP1B using p-nitrophenylphosphate (pNPP) assay. GA derivatives bearing substituted indoles or N-phenylpyrazoles fused to their A-ring showed a 50% inhibitory concentration for PTP1B in a range from 2.5 to 10.1 μM. The trifluo-romethyl derivative of indole-GA (4f) exhibited non-competitive inhibition of PTP1B as well as higher potency (IC50 = 2.5 μM) than that of positive controls ursolic acid (IC50 = 5.6 μM), claramine (IC50 = 13.7 μM) and suramin (IC50 = 4.1 μM). Finally, docking and molecular dynamics simulations provided the theoretical basis for the favorable activity of the designed compounds.
- Cortés-Benítez, Francisco,De-La-cruz-martínez, Ledy,Duran-Becerra, Constanza,Espinosa-Chávez, Julio,Germán-Acacio, Juan Manuel,González-Andrade, Martin,Páez-Franco, José C.,Pérez-Villanueva, Jaime,Palacios-Espinosa, Juan Francisco,Soria-Arteche, Olivia,Torres-Valencia, J. Martin
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- Glycyrrhetinic acid derivative Z-type isomer and preparation method thereof
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The invention discloses a glycyrrhetinic acid derivative Z-type isomer and a preparation method thereof. The method comprises the following steps: dissolving a glycyrrhetinic acid derivative E-type isomer in a mixed solvent of an organic solvent and water, and stirring under 254-380nm light to obtain the glycyrrhetinic acid derivative Z-type isomer. According to the method, through a green and healthy mode, no catalyst is used, and isomerization from the glycyrrhetinic acid derivative E-type isomer to the glycyrrhetinic acid derivative Z-type isomer is caused only in the mixed solution of the organic solvent and water by utilizing distortion and relaxation of a central double bond of the isomer under induction of a clean light energy source. The glycyrrhetinic acid derivative E-type isomer provided by the invention has relatively good stability and antibacterial property.
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Paragraph 0022; 0031; 0033; 0040; 0042; 0047; 0049; 0054...
(2021/09/04)
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- Structurally modified glycyrrhetinic acid derivatives as anti-inflammatory agents
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With the aim of finding new anti-inflammatory drugs, a series of new Glycyrrhetinic acid derivatives (1–34) have been designed and synthesized by structural modification, and their anti-inflammatory activities in vitro have been evaluated. The anti-inflammatory activities assay demonstrated that compound 5b suppressed the expression of pro-inflammatory cytokines including IL-6, TNF-α and NO, it also suppressed the expression of iNOS and COX-2 in LPS-induced RAW264.7 cells in a dose-dependent manner. Additionally, western blot results indicated that the suppressing effect of compound 5b on pro-inflammatory cytokines were correlated with the suppression of NF-κB and MAPK signaling pathways. The results attained in this study indicated that compound 5b had the potential to be developed into an anti-inflammation agent and it may be applied to the prevention and treatment of inflammatory diseases.
- Bian, Ming,Zhen, Dong,Shen, Qing-Kun,Du, Huan-Huan,Ma, Qian-Qian,Quan, Zhe-Shan
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- A versatile tailoring tool for pentacyclic triterpenes of Penicillium griseofulvum CICC 40293
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In the biosynthetic pathway of pentacyclic triterpenes (PTs), tailoring reactions can produce a wide range of end products from a small number of common scaffolds and the microbial transformation has also been established as an alternative technique for this purpose. In this study, we explored the tailoring reactions involved in the microbial transformation of pentacyclic triterpenes by Penicillium griseofulvum CICC 40293. Preparative biotransformation of eight different PTs from three scaffolds resulted in the isolation of thirteen metabolites. The structures of metabolites were elucidated by HR-ESI-MS, 1D, and 2D NMR spectroscopy. We discovered the highly efficient regio- and stereo-selective hydroxylation of inactivated sp3 CH2 and CH3 on the position of 2α, 7β, 15α, 21β, 23(angular methyl), and 30?COOH glycosylation, this versatile tailoring system for PTs would provide an effective method for expanding their structural diversities. In addition, all compounds were subjected to the bioassay on the model of lipopolysaccharide (LPS)-stimulated RAW 264.7 cells to evaluate their anti-inflammatory activity through nitric oxide (NO) inhibition activity. Compounds 2a and 5a exhibited excellent NO inhibitory activity with IC50 values of 8.35 ± 2.81 μM and 19.60 ± 4.25 μM, respectively.
- Zhu, Yuyuan,Shen, Pingping,Zhou, Xiaoyang,Fei, Yinuo,Wang, Wei,Raj, Richa,Du, Zhichao,Ge, Haixia,Wang, Weiwei,Xu, Shaohua,Yu, Boyang,Zhang, Jian
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p. 195 - 201
(2021/07/09)
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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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-
- 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 0046-0048
(2020/05/01)
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- Nitrogenous heterocyclic glycyrrhetinic acid derivatives, and preparation method and anti-influenza A virus application thereof
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The invention discloses nitrogenous heterocyclic glycyrrhetinic acid derivatives, and a preparation method and an anti-influenza A virus application thereof. The glycyrrhetinic acid derivatives comprise a nitrogen heterocyclic ring. A series of the glycyrrhetinic acid derivatives with anti-IAV activity are synthesized. The glycyrrhetinic acid derivatives have strong inhibitory activity on the influenza A virus (IAV), and have obviously stronger inhibitory activity on the influenza A virus than a common positive drug ribavirin, so that the glycyrrhetinic acid derivatives can be used for preparing anti-IAV drugs, and have no side effects.
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Paragraph 0031-0032; 0080-0082
(2020/02/29)
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- Drug design method based on natural product, pentacyclic triterpenoid compound, preparation method and application of pentacyclic triterpenoid compound
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The invention discloses a drug design method based on a natural product, a pentacyclic triterpenoid compound, and a preparation method and application of the pentacyclic triterpenoid compound. The design method comprises the following steps: (1) acquiring template molecules; (2) selecting a natural product which is similar to the template structure in a threshold range and has the specific biological activity as an alternative reference molecule set; (3) selecting one or more reference molecules from the reference molecule set, and comparing with the template molecule to obtain different active functional groups; and constructing the active functional groups with difference on a molecular skeleton which is commonly possessed by the template molecule and the reference molecule. According tothe invention, a cheap lead compound which is easy to obtain in quantity is successfully designed to replace triterpene molecules by taking the biological content of a plant triterpene natural product in a host plant and a numerical value similar to the structures of tripterine and a crosolic acid compound as screening conditions; experiments prove that the traditional Chinese medicine composition has obvious physiological activity of resisting inflammation and metabolic syndrome caused by chronic inflammation.
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Paragraph 0035; 0101-0107
(2020/09/16)
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- Nucleophilic (Radio)Fluorination of Redox-Active Esters via Radical-Polar Crossover Enabled by Photoredox Catalysis
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We report a redox-neutral method for nucleophilic fluorination of N-hydroxyphthalimide esters using an Ir photocatalyst under visible light irradiation. The method provides access to a broad range of aliphatic fluorides, including primary, secondary, and tertiary benzylic fluorides as well as unactivated tertiary fluorides, that are typically inaccessible by nucleophilic fluorination due to competing elimination. In addition, we show that the decarboxylative fluorination conditions are readily adapted to radiofluorination with [18F]KF. We propose that the reactions proceed by two electron transfers between the Ir catalyst and redox-active ester substrate to afford a carbocation intermediate that undergoes subsequent trapping by fluoride. Examples of trapping with O- and C-centered nucleophiles and deoxyfluorination via N-hydroxyphthalimidoyl oxalates are also presented, suggesting that this approach may offer a general blueprint for affecting redox-neutral SN1 substitutions under mild conditions.
- Webb, Eric W.,Park, John B.,Cole, Erin L.,Donnelly, David J.,Bonacorsi, Samuel J.,Ewing, William R.,Doyle, Abigail G.
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supporting information
p. 9493 - 9500
(2020/05/18)
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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 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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- 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 0156; 0157-0159
(2018/11/22)
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- Design, synthesis and biological evaluation of seco-A-pentacyclic triterpenoids-3,4-lactone as potent non-nucleoside HBV inhibitors
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A series of seco-A-pentacyclic triterpenoids-3,4-lactone were synthesized and the anti-HBV activities were evaluated in vitro. Several compounds inhibited the secretion of HBV antigen and the replication of HBV DNA in micromolar level. Compounds D7 and D10, seco-A-oleanane-3,4-lactone, suppressed the HBeAg secretion with IC50 values of 0.14 μM and 0.86 μM respectively, and the inhibitory activities were also confirmed by detecting the fluorescence intensity of FITC-labeled monoclonal mouse HBeAg antibody via flow cytometry. Compounds D7 and D10 as well as B4, ring-A cleaved 3,30-dioic acid, also displayed remarkable inhibition on both HBV DNA replication at the concentration of 25 μM and HBV cccDNA (covalently closed circularDNA) replication with IC50 values of 33.5 μM, 32.7 μM and 12.3 μM respectively.
- Li, Zhijian,Min, Qingxi,Huang, Haoji,Liu, Ruixuan,Zhu, Yongyan,Zhu, Quanhong
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supporting information
p. 1501 - 1506
(2018/04/20)
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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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- Matrine derivative having antitumor performance
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The invention relates to a matrine derivative, and provides a matrine derivative with characteristics of high activity, low toxicity and good antitumor performance, and uses of the matrine derivative in preparation of antitumor drugs.
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Paragraph 0073; 00740075
(2016/10/08)
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- GLYCYRRHETINIC ACID DERIVATIVE AND USE THEREOF
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Disclosed is a novel glycyrrhetinic acid derivative. The glycyrrhetinic acid derivative is represented by the following general formula (1).
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Paragraph 0039; 0053; 0055-0056
(2016/10/11)
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- Synthesis and biological evaluations of cytotoxic and antiangiogenic triterpenoids-jacaranone conjugates
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Background: The development of antiangiogenic agents arises as a more effective and selective therapeutic approach for the treatment of cancer. In addition to reduced acute toxicity, the efficacy of chemotherapy could be improved when administered in combination specific antiangiogenic with cytotoxic agents. The conjugation or hybridization of bifunctional molecules is one of the alternative rational design strategies for co-administration of anticancer drugs. Objective and Methods: The goal of this work is to prepare the conjugates of an antiangiogenic triterpene, 3-oxo oleanolic acid, and structurally related triterpenoids with a cytotoxic semibenzoquinone, jacaranone. The cytotoxic, antiproliferative and antiangiogenic activities of segments and conjugates were determined. The possible targets of conjugates 6a-6h were predicted using Similarity Ensemble Approach (SEA). Results: The results showed that these conjugates are more potent in both cytotoxic and antiangiogenic assays than their corresponding parent molecules, and are also selectively more active against melanoma cells B16 and metastatic B16BL6 than the two other cancer cell lines (A549 and MCF-7) tested. The predicted antiangiogenesis related targets could involve glycogen phosphorylase, neuraminidase, interferon gamma, and tubulin beta chain. Conclusion: The bifunctional conjugates could be useful as dual acting antitumor/antigiogenic agents.
- Sun, Hua,Yue, Partick Y.K.,Wang, Shao-Rong,Huo, Lihong,Zhao, Ying,Xie, Songbo,Kringelum, Jens V.,Lund, Ole,Taboureau, Olivier,Zhou, Jun,Wong, Ricky N. S.,Fang, Wei-Shuo
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p. 775 - 785
(2016/11/29)
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- GAOH derivative and its medical use
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The invention provides a GAOH derivative of a new structure. The compounds have great curative effects on inflammatory bowel diseases, hepatitis viruses, foot swelling, ear swelling, arthritis, pneumonia, nephritis, rhinitis, cerebral apoplexy, myocardial ischemia, atherosclerosis, arrhythmia, autoimmune disease, senile dementia, depression, schizophrenia, malignancy and tumor adjuvant therapy, virus infectious diseases, peptic ulcer, analgesia, antianaphylaxis, antiendotoxin, antishock and diabetes or diabetic complication.
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Paragraph 0038; 0039
(2016/11/17)
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- Synthesis of novel heterocyclic ring-fused 18β-glycyrrhetinic acid derivatives with antitumor and antimetastatic activity
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Glycyrrhetinic acid (GA) is one of the most important triterpenoic acids shows many pharmacological effects, especially antitumor activity. GA triggers apoptosis in various tumor cell lines. However, the antitumor activity of GA is weak, thus the synthesis of new synthetic analogs with enhanced potency is needed. By introducing various five-member fused heterocyclic rings at C-2 and C-3 positions, 18 novel GA derivatives were obtained. These compounds were evaluated for their inhibitory activity against the growth of eight different tumor cell lines using a SRB assay. The most active compound 37 showed IC 50 between 5.19 and 11.72 μm, which was about 11-fold more potent than the lead compound GA. An apoptotic effect of GA and 37 was determined using flow cytometry and trypan blue exclusion assays. We also demonstrated here for the first time that GA and the synthetic derivatives exhibited inhibitory effect on migration of the tested tumor cells, especially 37 which was about 20-fold more potent than GA on antimetastatic activity.
- Gao, Cheng,Dai, Fu-Jun,Cui, Hai-Wei,Peng, Shi-Hong,He, Yuan,Wang, Xue,Yi, Zheng-Fang,Qiu, Wen-Wei
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p. 223 - 233
(2014/07/22)
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- DERIVATIVE OF 18beta-GLYCYRRHETINIC ACID APT TO SUPPRESS CANCER CELLS
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The present invention is correlated with a derivative of 18β-glycyrrhetinic acid apt to suppressing cancer cells, which is selected from a group comprising of structure I and structure II: wherein residue R1 is selected from one of CH3 and CH2C6H5, residue R2 is selected from one of COOCH3, COOCH2CH3, COOCH(CH3)2, CONHCH2CH3, CONHCH2CH2CH3, and CONHCH2(CH3)2, and residue R3 is selected from one of COOCH2CH3, COOCH(CH3)2, CONHCH2CH3, CONHCH2CH2CH3, and CONHCH2(CH3)2.
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Paragraph 0028
(2013/05/09)
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- Improving the thrombin inhibitory activity of glycyrrhizin, a triterpenic saponin, through a molecular simplification of the carbohydrate moiety
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Glycyrrhizin, a saponin, and its aglycone glycyrrhetinic acid are natural products found in the Liquorice (Glycyrrhiza glabra L.) root extract. This saponin is known for its in vitro and in vivo thrombin inhibitory activity. The design and synthesis of five glycyrrhizin derivatives were carried out to improve the natural product activity. Compound 3b, a phthalic ester derivative of glycyrrhizin, presented a more pronounced thrombin inhibition (IC 50 = 114.4 ± 1.3 μm) than the saponin (IC50 = 235.7 ± 1.4 μm). Molecular docking simulations performed to investigate the molecular interaction between compound 3b and the enzyme indicate that this product is, as previously determined for glycyrrhizin, an allosteric thrombin inhibitor. We report in this article the semisynthesis and the in vitro thrombin inhibitory activity of the glycyrrhetinic acid hemiphthalic ester 3b. This activity was found to be more pronounced than of the saponin glycyrrhizin.
- De Paula, Fernando T.,Frauches, Petrina Q.,Pedebos, Conrado,Berger, Markus,Gnoatto, Simone C. B.,Gossmann, Grace,Verli, Hugo,Guimaraes, Jorge A.,Graebin, Cedric S.
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p. 756 - 760
(2014/01/06)
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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 of new glycyrrhetinic acid derived ring A azepanone, 29-urea and 29-hydroxamic acid derivatives as selective 11β-hydroxysteroid dehydrogenase 2 inhibitors
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Glycyrrhetinic acid, the metabolite of the natural product glycyrrhizin, is a well known nonselective inhibitor of 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1 and type 2. Whereas inhibition of 11β-HSD1 is currently under consideration for treatment of metabolic diseases, such as obesity and diabetes, 11β-HSD2 inhibitors may find therapeutic applications in chronic inflammatory diseases and certain forms of cancer. Recently, we published a series of hydroxamic acid derivatives of glycyrrhetinic acid showing high selectivity for 11β-HSD2. The most potent and selective compound is active against human 11β-HSD2 in the low nanomolar range with a 350-fold selectivity over human 11β-HSD1. Starting from the lead compounds glycyrrhetinic acid and the hydroxamic acid derivatives, novel triterpene type derivatives were synthesized and analyzed for their biological activity against overexpressed human 11β-HSD1 and 11β-HSD2 in cell lysates. Here we describe novel 29-urea- and 29-hydroxamic acid derivatives of glycyrrhetinic acid as well as derivatives with the Beckman rearrangement of the 3-oxime to a seven-membered ring, and the rearrangement of the C-ring from 11-keto-12-ene to 12-keto-9(11)-ene. The combination of modifications on different positions led to compounds comprising further improved selective inhibition of 11β-HSD2 in the lower nanomolar range with up to 3600-fold selectivity.
- Gaware, Rawindra,Khunt, Rupesh,Czollner, Laszlo,Stanetty, Christian,Cunha, Thierry Da,Kratschmar, Denise V.,Odermatt, Alex,Kosma, Paul,Jordis, Ulrich,Cla?en-Houben, Dirk
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scheme or table
p. 1866 - 1880
(2011/05/02)
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- Synthesis and antitumor activity of ring a-modified glycyrrhetinic acid derivatives
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The pentacyclic triterpene glycyrrhetinic acid is an interesting natural product exhibiting various biological activities. Especially its ability to induce apoptosis in tumor cells is of high scientific interest. In this study we altered the lipophilicity in ring A by derivatization at positions C-2 and C-3. The consequences of these variations on the cytotoxicity were investigated applying a colorimetric sulforhodamine B assay using 8 different human tumor cell lines. An acridine orange/ethidium bromide (AO/EB) test and a trypan blue test were used to determine the extent of apoptotic activity of some of these compounds.
- Csuk, Rene,Schwarz, Stefan,Siewert, Bianka,Kluge, Ralph,Stroehl, Dieter
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experimental part
p. 521 - 532
(2011/07/09)
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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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- 18β-Glycyrrhetinic acid derivatives induced mitochondrial-mediated apoptosis through reactive oxygen species-mediated p53 activation in NTUB1 cells
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Twenty six 18β-glycyrrhetinic acid (GA) (1) derivatives 2-27 including twelve new GA derivatives 10, 11, 13-17, 21-25 were synthesized and evaluated for cytotoxicities against NTUB1 cells (human bladder cancer cell lines). seco-Compounds 9, 25, and 27 are the most potent compounds of this series, inhibiting cell growth of human NTUB1 cells with an IC50 values of 2.34 ± 0.28, 4.76 ± 1.15, and 3.31 ± 0.61 μM, respectively. Exposure of NTUB1 to 25 for 24 h significantly increased the production of reactive oxygen species (ROS). Flow cytometric analysis exhibited that treatment of NTUB1 with 25 did not induce cell cycle arrest but accompanied by an increase of apoptotic cell death in a dose-dependant manner after 24 h. Mitochondrial membrane potential (MMP) decreased significantly in a dose-dependant manner when the NTUB1 cells were exposed to 25 for 24 h. Marked collapse of the MMP suggested that dysfunction of the mitochondria may be involved in the oxidative burst and apoptosis induced by 25. Western blot analysis shows that NTUB1 cells treated with 25 increased the level of p-p53 in a dose-dependant manner. Further, NAC treatment prevented p53 phosphorylation stimulated by 25. These results suggested that 25 induced a mitochondrial- mediated apoptosis in NTUB1 cells through activation of p53, which are mainly mediated ROS generated by 25.
- Lin, Kai-Wei,Huang, A-Mei,Hour, Tzyh-Chyuan,Yang, Shyh-Chyun,Pu, Yeong-Shiau,Lin, Chun-Nan
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scheme or table
p. 4274 - 4285
(2011/08/21)
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- The synthesis of glycyrrhetinic acid derivatives containing a nitrogen heterocycle and their antiproliferative effects in human leukemia cells
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Fifteen novel glycyrrhetinic acid derivatives containing a nitrogen heterocycle at C-30 and with different A-ring substituents were designed and synthesized. All of these derivatives have improved antiproliferative effects against human HL-60 leukemia cells. Compounds with a cyano-enone functionality on the A-ring exhibit greater growth inhibitory effects, compared to those with a 2-hydroxymethylene-3-keto, an isoxazole, or a 2-cyano-3-keto group. N-(2-cyano-3,11-dioxoolean-1,12-dien-30-yl)-4-piperidyl piperidine (9b) was found to be two-fold more potent than methyl 2-cyano-3,11-dioxooleana-1,12-dien- 30-oate (CDODO-Me-11).
- Gao, Yuan,Guo, Xin,Li, Xiaojing,Liu, Dan,Song, Dandan,Xu, Ye,Sun, Ming,Jing, Yongkui,Zhao, Linxiang
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experimental part
p. 4439 - 4449
(2010/10/03)
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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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- Bioactive microbial metabolites from glycyrrhetinic acid
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Biotransformation of 18β-glycyrrhetinic acid, using Absidia pseudocylinderospora ATCC 24169, Gliocladium viride ATCC 10097 and Cunninghamella echinulata ATCC 8688a afforded seven metabolites, which were identified by different spectroscopic techniques (1H, 13C NMR, DEPT, 1H-1H COSY, HMBC and HMQC). Three of these metabolites, viz. 15α-hydroxy-18α-glycyrrhetinic acid, 13β-hydroxy-7α,27-oxy-12-dihydro-18β-glycyrrhetinic acid and 1α-hydroxy-18β-glycyrrhetinic acid are new. The 13C NMR data and full assignment for the known metabolite 7β, 15α-dihydroxy-18β-glycyrrhetinic acid are described here for the first time. The major metabolites were evaluated for their hepatoprotective activity using different in vitro and in vivo models. These included protection against FeCl3/ascorbic acid-induced lipid peroxidation of normal mice liver homogenate, induction of nitric oxide (NO) production in rat macrophages and in vivo hepatoprotection against CCl4-induced hepatotoxicity in albino mice.
- Maatooq, Galal T.,Marzouk, Amani M.,Gray, Alexander I.,Rosazza, John P.
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experimental part
p. 262 - 270
(2010/05/17)
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- Synthesis and evaluation of A-seco type triterpenoids for anti-HIV-1protease activity
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2,3-Seco-dioic acids derived from four different triterpene skeletons were prepared and evaluated for their anti-HIV-1 protease activity. Two A-seco derivatives showed potent inhibitory activity against HIV-1 protease (3c and 3e, IC50 5.7 and 3.9 μM, respectively), while four other derivatives showed moderate to weak inhibition (3a, 3b, 3d and 3f, IC50 15.7-88.1 μM). The combination of a 2,3-seco-2,3-dioic acid functional group in ring A and a free acid group at C-28 or C-30 significantly enhanced HIV-1 protease inhibitory activity (3a, 3c-3e, IC50 3.9-17.6 μM). On the other hand, all A-seco derivatives were found to be very weak inhibitors of HCV, renin and trypsin proteases (IC50 > 80 μM). These findings indicate that A-seco triterpenes with a carboxyl group at C-28 or C-30 are novel and highly selective HIV-1 protease inhibitors.
- Wei, Ying,Ma, Chao-Mei,Hattori, Masao
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experimental part
p. 4112 - 4120
(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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- Chemical modifications of natural triterpenes-glycyrrhetinic and boswellic acids: evaluation of their biological activity
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Synthetic analogues of naturally occurring triterpenoids; glycyrrhetinic acid, arjunolic acid, and boswellic acids, by modification of A-ring with a cyano- and enone-functionality, have been reported. A novel method of synthesis of α-cyanoenones from isoxazoles is reported. Bioassays using primary mouse macrophages and tumor cell lines indicate potent anti-inflammatory and cytotoxic activities associated with cyano-enones of boswellic acid and glycyrrhetinic acid.
- Subba Rao,Kondaiah, Paturu,Singh, Sanjay K.,Ravanan, Palaniyandi,Sporn, Michael B.
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experimental part
p. 11541 - 11548
(2009/04/06)
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- Novel 18β-glycyrrhetinic acid analogues as potent and selective inhibitors of 11β-hydroxysteroid dehydrogenases
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Extensive structural modifications to the 18β-glycyrrhetinic acid template are described and their effects on the SAR of the 11β- hydroxysteroid dehydrogenase isozymes type 1 and 2 from the rat are investigated. Isoform selective inhibitors have been discovered and compound 7 N-(2-hydroxyethyl)-3β-hydroxy-11-oxo-18β-olean-12-en-30-oic acid amide is highlighted as a very potent selective inhibitor of 11β-hydroxysteroid dehydrogenase 2 with an IC50=4pM.
- Su, Xiangdong,Lawrence, Harshani,Ganeshapillai, Dharshini,Cruttenden, Adrian,Purohit, Atul,Reed, Michael J.,Vicker, Nigel,Potter, Barry V.L.
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p. 4439 - 4457
(2007/10/03)
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- Simultaneous determination of glycyrrhizin metabolites formed by the incubation of glycyrrhizin with rat feces by semi-micro high-performance liquid chromatography
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A method for semi-micro high-performance liquid chromatography (HPLC) has been established for the simultaneous determination of 3α- hydroxyglycyrrhetic acid and 3-dehydroglycyrrhetic acid together with glycyrrhizin, glycyrrhetic acid and glycyrrhetic acid mono-glucuronide formed by incubation of glycyrrhizin with rat feces. The analysis was accomplished within 25 min with a TSKgel ODS-80TsQA (150 x 2.0 mm i.d.) column by linear gradient elution using a mobile phase containing aqueous phosphoric acid and acetonitrile at a flow rate of 0.2 ml·min-1, a thermostatic oven at 25°C, and detection at 254 nm. The detection limits of these compounds were 0.2 pmol per injection (5 μl). The metabolites of glycyrrhizin, by anaerobic or aerobic incubation with rat fecal suspension over 48 h, were determined. Glycyrrhizin was almost completely converted to metabolite glycyrrhetic acid, and metabolites 3α-hydroxyglycyrrhetic acid and 3-dehydroglycyrrhetic acid in negligible amounts in anaerobic conditions. However, the metabolic time courses of 3-dehydroglycyrrhetic acid when incubated in aerobic conditions revealed that it apparently continued increasing during the whole incubation period.
- Okamura, Nobuyuki,Miyauchi, Hidetoshi,Choshi, Tominari,Ishizu, Takashi,Yagi, Akira
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p. 658 - 661
(2007/10/03)
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- Influence of honey on the gastrointestinal metabolism and disposition of glycyrrhizin and glycyrrhetic acid in rabbits.
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To investigate the effects of honey on the pharmacokinetics of glycyrrhizin and glycyrrhetic acid, administration of glycyrrhizin or glycyrrhetic acid with and without honey was carried out in rabbits in a randomized crossover design. An in vitro study using rabbit fecal flora was employed to elucidate the mechanism of the interaction. HPLC methods were used for the determination of glycyrrhizin, glycyrrhetic acid and 3-dehydroglycyrrhetic acid concentrations in serum and feces. Paired and unpaired Student's t-tests were used for statistical comparisons for in vivo and in vitro studies, respectively. Our study indicated that the area under the curve (AUC0-t) of glycyrrhetic acid was significantly enhanced by 53% when honey was concomitantly given with glycyrrhizin, whereas that of glycyrrhizin was not significantly altered. Nevertheless, lack of effect was observed when honey was concurrently given with glycyrrhetic acid. Fecal study indicated that both the hydrolysis of glycyrrhizin to glycyrrhetic acid and subsequent oxidation of glycyrrhetic acid to 3-dehydroglycyrrhetic acid were significantly affected in the presence of honey to result in more glycyrrhetic acid available for absorption. It could be concluded that honey significantly affected the gastrointestinal metabolism of glycyrrhizin and resulted in the increased glycyrrhetic acid exposure. Therefore, honey might enhance the efficacy and adverse effects of glycyrrhizin.
- Ching, Hui,Hou, Yu-Chi,Hsiu, Su-Lan,Tsai, Shang-Yuan,Chao, Pei-Dawn Lee
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- Terpenoid Chirons: Preparation and Transformations of 2-Hydroxy-1,1,4a(R),6-Tetramethyl-Trans-Δ5,6-Octalin
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Octalins 4 and 5 are prepared conveniently in 3 steps from commercial 18β-glycyrrhetinic acid and converted to a variety of functionalized trans AB ring chirons.KEYWORDS: thermolysis, steroid, octahydronaphthalene, retro-Diels-Alder, glycyrrhetinic acid
- Falck, J. R.,Manna, Sukumar,Chandrasekhar, S.,Alcaraz, L.,Mioskowski, C.
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p. 2013 - 2016
(2007/10/02)
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