Synthesis and antitumor activity of ring A modified glycyrrhetinic acid derivatives

Csuk, René; Schwarz, Štefan; Siewert, Bianka; Kluge, Ralph; Ströhl, Dieter

doi:10.1016/j.ejmech.2011.08.038

Cited by 64 publications

(39 citation statements)

References 27 publications

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“…This parallels previous findings for other triterpenoids, for example, glycyrrhetinic acid, 28 boswellic acid, 45,46 oleanolic [47][48][49] or usolic acid, 41 where the introduction of an amino group at position C-3 led to highly increased cytotoxicity. High cytotoxicity for tumor cells, however, is not sufficient to make a compound ready for broader biological screening; a low cytotoxicity for non-malignant cells is mandatory.…”

Section: Biologysupporting

confidence: 87%

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Simple structural modifications confer cytotoxicity to allobetulin

Heller

Obernauer

Csuk

2015

Bioorganic & Medicinal Chemistry

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Section: Biologysupporting

confidence: 87%

“…27 As previously shown for several pentacyclic triterpenoids, the presence of an amino group at position C-3 seems favorable and enhances cytotoxicity. [28][29][30] Hence, we decided to investigate allobetulin and derivatives thereof in more detail.…”

Section: Introductionmentioning

confidence: 99%

Simple structural modifications confer cytotoxicity to allobetulin

Heller

Obernauer

Csuk

2015

Bioorganic & Medicinal Chemistry

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“…These compounds are characterized in their 13 C NMR spectra by the presence of a C = O carbon whose chemical shift was detected between  = 217.2-217.0 ppm, respectively. These amides 13-17 were allowed to react with hydroxylammonium chloride in dry pyridine at 60 °C for 3 hours 7 followed by a precipitation of the crude product by adding 1 M aqueous hydrochloric acid. Re-crystallization from methanol or chromatography yielded oximes 18-22, respectively.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and cytotoxicity of 3-amino-glycyrrhetinic acid derivatives

Sahn¹,

Grupe²,

Heller³

et al. 2018

Mediterr.J.Chem.,

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The aim of this study was to prepare 3-hydroximino- and 3-amino derivatives of glycyrrhetinic acid and derivatives to evaluate their in vitro cytotoxicity for a panel of human tumor cell lines. Thus, commercially available glycyrrhetinic acid (1) was acetylated or oxidized at position C-3 and transformed into a variety of different esters and amides followed by their conversion to 3-oximes and amines. While the parent compound was not cytotoxic at all, the 3-amino esters are highly cytotoxic. Interestingly, 3-amino amides were significantly less cytotoxic than 3-amino esters. The (3b, 18b, 20b) Benzyl 3-amino-11-oxoolean-12-en-30-oate was the most cytotoxic compound of this series showing an EC50 = 1.3 mM for 518A2 melanoma cells.

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“…(L-Isoleucine Methyl Ester)-3E-acetyl-11-oxo-olean-12-en-18E-H-30-amide(4). Yield 62% (white powder).…”

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confidence: 99%

“…The potential to produce new biologically active compounds through chemical modification of GLA has not been fully explored [2][3][4][5].…”

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Synthesis and Antiviral Activity of Amino-Acid Conjugates of Glycyrrhetic Acid

et al. 2014

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Conjugates of glycyrrhetic acid (GLA) with amino acids (L-isoleucine, -leucine, -valine, and -phenylalanine) were synthesized by the acid-chloride method using methyl or tert-butyl esters of the acids. Tests in MDCK cell culture showed that the GLA conjugate with phenylalanine exhibited high antiviral activity against influenza A/H1N1/pdm09 virus (ED 50 =4.4 Pg/mL, SI = 161).Chemical modification of plant triterpenoids has in the last decade produced a whole series of lead compounds that are medically promising as new antitumor, antiviral, and antidiabetic agents.The pentacyclic triterpenoid glycyrrhetic acid (GLA, 1) is the product from acid and enzymatic hydrolysis of glycyrrhizic acid, the principal constituent of Glycyrrhiza glabra L. and G. uralensis Fisher roots, and is a promising natural product for creating new drugs to treat and prevent oncological and inflammatory diseases, hepatoprotectors, antioxidants, antiulcer and antiviral agents, etc.[1]. The potential to produce new biologically active compounds through chemical modification of GLA has not been fully explored [2][3][4][5].In continuation of our research on the synthesis of new biologically active GLA derivatives, we synthesized aminoacid conjugates using GLA 3-O-acetate (2) as starting material. It was converted into acid chloride 3 via reaction with thionylchloride (SOCl 2 ) in benzene (Scheme 1). The amino acids were methyl or tert-butyl (t-Bu) esters of L-amino acid hydrochlorides and were acylated via reaction with 3 in CH 2 Cl 2 in the presence of Et 3 N or N-methylmorpholine (NMM) to afford conjugates 4-8 in 60-70% yields. The yields of the protected conjugates were higher if the amino-acid t-Bu esters were used as the amines.Analytically pure 4 and 5 were isolated by column chromatography (CC) over silica gel (SG). Conjugates 6-8 were reprecipitated from aqueous EtOH. The protecting groups were removed without further purification.Conjugates 4 and 5 in dioxane:MeOH were treated with aqueous NaOH (4 N) and acidified subsequently with HCl solution (5%) in order to remove the 3-O-acetyl and methyl ester. The t-Bu ester protecting group of 6-8 was removed by trifluoroacetic acid (TFA) in CH 2 Cl 2 at 20-22°C. Then, the 3-O-acetyl protection was removed in dioxane by alkaline hydrolysis using aqueous NaOH (4 N). The resulting compounds were chromatographed over SG to afford free GLA conjugates 9-12 containing free amino acids L-isoleucine (Ile), -leucine (Leu), -valine (Val), and -phenylalanine (Phe) in 53-57% yields.

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Synthesis and antitumor activity of ring A modified glycyrrhetinic acid derivatives

Cited by 64 publications

References 27 publications

Simple structural modifications confer cytotoxicity to allobetulin

Simple structural modifications confer cytotoxicity to allobetulin

Synthesis and cytotoxicity of 3-amino-glycyrrhetinic acid derivatives

Synthesis and Antiviral Activity of Amino-Acid Conjugates of Glycyrrhetic Acid

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