Synthesis and biological activity of new 18β-glycyrrhetinic acid derivatives

Radwan, Mohamed O.; Ismail, Mohamed A.H.; El‐Mekkawy, Sahar; Ismail, Nasser S. M.; Hanna, Atef G.

doi:10.1016/j.arabjc.2013.06.032

Cited by 33 publications

(28 citation statements)

References 18 publications

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“…17,18) Some of these triterpenoids were reported to exhibit anti-tyrosine kinase activity. 19,20) Here we focused on a pentacyclic triterpenoid gypsogenin, 21,22) extracted from Gypsophila species, 23,24) which is widely distributed in the Eurasian continent.…”

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confidence: 99%

The First Pentacyclic Triterpenoid Gypsogenin Derivative Exhibiting Anti-ABL1 Kinase and Anti-chronic Myelogenous Leukemia Activities

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Öztürk

Ali

et al. 2018

Biological & Pharmaceutical Bulletin

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SummaryThe discovery of the chimeric tyrosine kinase breakpoint cluster region kinase-Abelson kinase (BCR-ABL)-targeted drug imatinib conceptually changed the treatment of chronic myelogenous leukemia (CML). However, some CML patients show drug resistance to imatinib. To address this issue, some artificial heterocyclic compounds have been identified as BCR-ABL inhibitors. Here we examined whether plant-derived pentacyclic triterpenoid gypsogenin and/or their derivatives show inhibitory activity against BCR-ABL. Among the three derivatives, benzyl 3-hydroxy-23-oxoolean-12-en-28-oate (1c) was found to be the most effective anticancer agent on the CML cell line K562, with an IC 50 value of 9.3 µM. In contrast, the IC 50 against normal peripheral blood mononuclear cells was 276.0 µM, showing better selectivity than imatinib. Compound 1c had in vitro inhibitory activity against Abelson kinase 1 (ABL1) (IC 50 =8.7 μM), the kinase component of BCR-ABL. In addition, compound 1c showed a different inhibitory profile against eight kinases compared with imatinib. The interaction between ATP binding site of ABL and 1c was examined by molecular docking study, and the binding mode was different from imatinib and newer generation inhibitors. Furthermore, 1c suppresses signaling downstream of BCR-ABL. This study suggests the possibility that plant extracts may be a source for CML treatment and offer a strategy to overcome drug resistance to known BCR-ABL inhibitors. KeywordsGypsogenin, Abelson tyrosine-protein kinase 1, chronic myelogenous leukemia Biological and Pharmaceutical Bulletin Advance PublicationCancer is a worldwide health problem, and despite intensive research efforts over the last several decades, an effective cure has not been identified. 1)However, the recent discovery of molecular targeted drugs against cancer at the end of the 20 th century has led to promising results. 1,2) Imatinib (Fig. 1), which targets the chimeric tyrosine kinase breakpoint cluster region kinase-Abelson kinase (BCR-ABL), [3][4][5][6] was discovered based on the findings that chronic myelogenous leukemia (CML) is caused by a chromosomal translocation that results in the constitutively expressed and active BCR-ABL. 7,8) While imatinib can be initially effective in treating CML, some patients have shown drug resistance to imatinib. [9][10][11] Several new generation drugs with a different binding mode to Abelson kinase (ABL) have thus been developed. 6,[12][13][14][15][16] These drugs are artificial heterocyclic compounds, however, if widely distributed natural products and/or their derivatives show the inhibitory activity against BCR-ABL, it would be more convenient to get.Pentacyclic triterpenoids, a category of natural compounds, can be extracted from a variety of plants and show various activities. 17,18) Some of these triterpenoids were reported to exhibit anti-tyrosine kinase activity. 19,20) Here we focused on a pentacyclic triterpenoid gypsogenin, 21,22) extracted from Gypsophila species, 23,24) which is widely distributed in the Eu...

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confidence: 99%

The First Pentacyclic Triterpenoid Gypsogenin Derivative Exhibiting Anti-ABL1 Kinase and Anti-chronic Myelogenous Leukemia Activities

Çiftçi

Öztürk

Ali

et al. 2018

Biological & Pharmaceutical Bulletin

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“…2) Glycyrrhetinic acid (GA, see Fig. 1), which is isolated from Glycyrrhiza uralensis Fisch, Glycyrrhiza inflata Batalin and G. glabra L. and is the main biologically active component of these plants, and GA derivatives show a variety of pharmaceutical effects, for example, anticancer, [3][4][5][6][7] anti-oxidation, 8) antiinflammatory, 9,10) antiviral [11][12][13][14] and anti-ulcer 15) properties, etc. In our previous work, we have reported on antitumor activity of derivatives of GA, and some of these compounds showed better anti-tumor activity than GA itself and Gefitinib.…”

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confidence: 99%

Design, Preparation and Studies Regarding Cytotoxic Properties of Glycyrrhetinic Acid Derivatives

Wang

et al. 2020

Biological & Pharmaceutical Bulletin

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Glycyrrhetinic acid (GA) is a natural product with certain antitumor activity. In order to enhance the cytotoxicity, a total of eighteen derivatives of GA were designed and synthesized. Their cytotoxicity against MDA-MB-231cells (human breast cancer cells) and HeLa cells (human cervical cancer cells), were evaluated by the MTT method (3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide). The results indicated that these target compounds have a wide molar activity range and some of them show better activity than the commercial drugs gefitinib and doxorubicin. Compound 6g induces apoptosis of 7, 10 and 44% of MDA-MB-231 cells at 5, 10, and 20 µM, respectively.

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“…Stearyl glycyrrhetinate (SG), the stearyl ester of 18-β-glycyrrhetinic acid, is a derivative of GA. It has been demonstrated that GA and its derivatives may be used as ligands targeting the liver (Radwan et al., 2016; Zhu et al., 2018). Because it has been shown that abundant receptors for GA exist on liver cell membranes, several recent research efforts have attempted to utilize GA as a targeting ligand for hepatocyte-targeting (He et al., 2010; Huang et al., 2011; Shi et al., 2012; He et al., 2014; Zhang et al., 2015; Chen et al., 2015b).…”

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confidence: 99%

Preparation and in vitro and in vivo evaluations of 10-hydroxycamptothecin liposomes modified with stearyl glycyrrhetinate

et al. 2019

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10-Hydroxycamptothecin (HCPT) liposomes surface modified with stearyl glycyrrhetinate (SG) were prepared by the film dispersion method. Characterization of the liposomes, including drug release in vitro , pharmacokinetics and tissue distribution, was done. HCPT in plasma and tissues was determined by high-performance liquid chromatography (HPLC). Compared with the conventional HCPT-liposomes and commercially available hydroxycamptothecin injection (HCPT Inject), pharmacokinetic parameters indicated that SG-HCPT-liposomes had better bioavailability. Regarding tissue distribution, the concentration of HCPT loaded by SG modified liposomes in the liver was higher than other tissues and the risk to the kidney was lower than HCPT-liposomes and HCPT Inject. These results support the hypothesis that the HCPT-liposomes modified with SG show enhanced liver-targeting through the glycyrrhetinic acid (GA) receptor to be an efficient drug carrier, which may help to improve therapeutic methods for hepatic diseases in the future.

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Synthesis and biological activity of new 18β-glycyrrhetinic acid derivatives

Cited by 33 publications

References 18 publications

The First Pentacyclic Triterpenoid Gypsogenin Derivative Exhibiting Anti-ABL1 Kinase and Anti-chronic Myelogenous Leukemia Activities

The First Pentacyclic Triterpenoid Gypsogenin Derivative Exhibiting Anti-ABL1 Kinase and Anti-chronic Myelogenous Leukemia Activities

Design, Preparation and Studies Regarding Cytotoxic Properties of Glycyrrhetinic Acid Derivatives

Preparation and in vitro and in vivo evaluations of 10-hydroxycamptothecin liposomes modified with stearyl glycyrrhetinate

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