Design and Synthesis of New Anticancer Glycyrrhetinic Acids and Oleanolic Acids

Wang, Rui; Wang, Wei; Feng, Ling; Huai, Qing

doi:10.1248/bpb.b17-00016

Cited by 10 publications

(7 citation statements)

References 26 publications

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“…The organic phase was washed with water until pH = 7, dried over anhydrous sodium sulfate, filtered and concentrated under vacuo. The resulted residue was applied for column chromatography using an appropriate eluent [31].…”

Section: Methodsmentioning

confidence: 99%

“…Glycyrrhetic acid benzyl ester ( PT3 ) [31,38]. Compound PT3 was obtained from GA and benzyl bromide as a white solid (123 mg, 44%).…”

Section: Methodsmentioning

confidence: 99%

“…Among them, pentacyclic triterpenes are the subjects of numerous studies carried out by chemists engaged in organic synthesis and pharmacology. A large number of pentacyclic triterpenes such as glycyrrhetic acid, oleanolic acid, ursolic acid, betulinic acid and their derivatives have been reported to exhibit various biological activities including antiinflammatory, antimicrobial, antiviral, antioxidant, antitumor and anticancer [27,28,29,30,31,32]. However, a pentacyclic triterpene named gypsogenin has not yet received significant attention in drug discovery.…”

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis and Biological Evaluation of Pentacyclic Triterpene Derivatives: Optimization of Anti-ABL Kinase Activity

et al. 2019

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Imatinib, an Abelson (ABL) tyrosine kinase inhibitor, is a lead molecular-targeted drug against chronic myelogenous leukemia (CML). To overcome its resistance and adverse effects, new inhibitors of ABL kinase are needed. Our previous study showed that the benzyl ester of gypsogenin (1c), a pentacyclic triterpene, has anti-ABL kinase and a subsequent anti-CML activity. To optimize its activities, benzyl esters of carefully selected triterpenes (PT1–PT6), from different classes comprising oleanane, ursane and lupane, and new substituted benzyl esters of gypsogenin (GP1–GP5) were synthesized. All of the synthesized compounds were purified and charachterized by different spectroscopic methods. Cytotoxicity of the parent triterpenes and the synthesized compounds against CML cell line K562 was examined; revealing three promising compounds PT5, GP2 and GP5 (IC50 5.46, 4.78 and 3.19 μM, respectively). These compounds were shown to inhibit extracellular signal-regulated kinase (ERK) downstream signaling, and induce apoptosis in K562 cells. Among them, PT5 was identified to have in vitro activity (IC50 = 1.44 μM) against ABL1 kinase, about sixfold of 1c, which was justified by molecular docking. The in vitro activities of GP2 and GP5 are less than PT5, hence they were supposed to possess other more mechanisms of cytotoxicity. In general, our design and derivatizations resulted in enhancing the activity against ABL1 kinase and CML cells.

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Section: Methodsmentioning

confidence: 99%

“…Glycyrrhetic acid benzyl ester ( PT3 ) [31,38]. Compound PT3 was obtained from GA and benzyl bromide as a white solid (123 mg, 44%).…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis and Biological Evaluation of Pentacyclic Triterpene Derivatives: Optimization of Anti-ABL Kinase Activity

et al. 2019

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“…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. [16][17][18] However, one of the limiting factors for the application of glycyrrhetinic acid is that its biological activity is too low. It has been reported 19) that the esterification of C30 carboxyl groups could increase the antitumor activity of glycyrrhetinic acid.…”

Section: Introductionmentioning

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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“…[21][22][23][24][25] To further explore the physiological activities of OA and GA, researchers performed a large number of structural modifications and studies of biological activities on these two natural products. [26][27][28][29][30] Through previous reports, we think that through structural modification to improve the anticancer activity of OA and GA is appropriate. Chu et al reported the first preparation of ligustrazine-oleanolic acid and then the introduction of amino acid fragments to obtain new compounds with high inhibitory activities.…”

Section: Introductionmentioning

confidence: 99%

Design and preparation of derivatives of oleanolic and glycyrrhetinic acids with cytotoxic properties

Wang¹,

Yang²,

Huai³

et al. 2018

DDDT

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BackgroundThe structural modification of natural products with the aim to improve the anticancer activity is a popular current research direction. The pentacyclic triterpenoid compounds oleanolic acid (OA) and glycyrrhetinic acid (GA) are distributed widely in nature.MethodsIn this study, various oleanolic acids and glycyrrhetinic acids were designed and synthesized by using the combination principle. The in vitro anticancer activities of new OA and GA derivatives were tested by the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) method with SGC-7901 (gastric cancer), MCF-7 (breast cancer), Eca-109 (esophageal cancer), HeLa (cervical cancer), Hep-G2 (hepatoma cancer) and HSF (normal human skin fibroblast) cells.Results and conclusionThe screening results showed that the compound 3m presented the highest inhibitory activities against SGC-7901, MCF-7 and Eca-109 cell lines with IC50 values of 7.57±0.64 μM, 5.51±0.41 μM and 5.03±0.56 μM, respectively. In addition, this compound also showed effective inhibition of Hep-G2 cells with an IC50 value of 4.11±0.73 μM. Moreover, compound 5b showed the strongest inhibitory activity against Hep-G2 cells with an IC50 value of 3.74±0.18 μM and compound 3l showed strong selective inhibition of the HeLa cells with the lowest IC50 value of 4.32±0.89 μM. A series of pharmacology experiments indicated that compound 5b could induce Hep-G2 cells autophagy and apoptosis. These compounds will expand the structural diversity of anti-cancer targets and confirm the prospects for further research.

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Design and Synthesis of New Anticancer Glycyrrhetinic Acids and Oleanolic Acids

Cited by 10 publications

References 26 publications

Design, Synthesis and Biological Evaluation of Pentacyclic Triterpene Derivatives: Optimization of Anti-ABL Kinase Activity

Design, Synthesis and Biological Evaluation of Pentacyclic Triterpene Derivatives: Optimization of Anti-ABL Kinase Activity

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

Design and preparation of derivatives of oleanolic and glycyrrhetinic acids with cytotoxic properties

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