R. M. Kondratenko

Synthesis and high-resolution NMR spectra of A-nor-derivatives of 11-deoxyglycyrrhetic acid

Several skeletal and oxidative transformations of 11-deoxyglycyrrhetic acid were carried out to produce A-nor-derivatives. Signals for protons and C atoms in the PMR and 13C NMR spectra of the A-nor-derivatives were assigned using high-resolution 1H (400 MHz) and 13C (125 MHz) NMR spectroscopy.

Synthesis of new derivatives of 3β-hydroxy18βH-olean-9,12-dien-30-oic acid

Ring A was transformed and new A-homo-4-aza- and 3-cyano-3,4-seco-olean-4-ene derivatives of 3β-hydroxy18βH-olean-9,12-dien-30-oic acid were synthesized.

Synthesis of glycyrrhizic acid conjugates containing L-lysine

Activated esters and N-hydroxybenzotriazole-N,N′-dicyclohexylcarbodiimide (DCC) or N-hydroxysuccinimide-DCC were used to synthesize conjugates of glycyrrhizic acid (GA) with Nɛ-carbobenzyloxy-L-lysine [Lys(Z)-OH] and its esters containing two or three amino components. It was shown that the conjugate of GA 30-methyl ester with Lys(Z)-OH possessed anti-HIV-1 activity.

Obtaining Glycyrrhizic Acid and Its Practically Useful Salts from a Commercial Licorice Root Extract

We describe an optimized method for obtaining glycyrrhizic acid (GA, 90.5 ± 1.5%), which is the main triterpene glycoside of licorice root (Glycyrrhiza glabra L., Gl. uralensis Fisher) extract, and its trisodium and monoammonium salts from a commercial licorice root extract containing 20.0 ± 1.5% GA.

The Synthesis and Antiviral Activity of Glycyrrhizic Acid Conjugates with α-D-Glucosamine and Some Glycosylamines

Glycyrrhizic acid and its 30-methyl ester were conjugated with 2-amino-1,3,4,6-tetra-O-acetyl-2-deoxy-α-D-glucopyranose, 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl amine, 2,3,4-tri-O-acetyl-α-L-arabinopyranosyl amine, 2-acetamido-2-deoxy-β-D-glucopyranosyl amine, and β-D-galactopyranosyl amine using N,N′-dicyclohexylcarbodiimide and its mixtures with N-hydroxybenzotriazole. Structures of the conjugates were confirmed by IR, UV, 1H, and 13C NMR spectroscopy. The glycoconjugate with the residues of 2-acetamido-2-deoxy-β-D-glucopyranosyl amine in the carbohydrate part of its molecule exhibited antiviral activity (ID50 4 μg/ml) toward the herpes simplex type 1 virus (HSV-1) in the VERO cell culture. Two compounds demonstrated anti-HIV-1 activity (50–70% inhibition of p24) in a culture of MT-4 cells at concentrations of 0.5–20 μg/ml.

13C NMR spectra of a number of penta- and hexacyclic triterpenoids derived from glycyrrhetic acid

The13C NMR spectra of 22 derivatives of 18α- and 18β-glycyrrhetic acids that have been investigated and an assignment of the signals has been made. It has been shown that a modification of the carboxy group of glycyrrhetic acid leads mainly to a change in the chemical shifts of the α-, β-, and γ-carbon atoms of ring E. The assignment of a number of signals has been confirmed by the use of the shift reagent Eu(fod)s. It has been established that the C28 and C16 signals are the most sensitive to a change in the C18 configuration in the spectra of glycyrrhetic acid derivatives.

Synthesis of new hetero- and carbocyclic aromatic amides of glycyrrhizic acid as potential anti-HIV agents

Members of a new group of di- and trisubstituted amides of glycyrrhizic acid (GA), the major component of licorice root extract, were synthesized; derivatives contained fragments of heterocyclic and aromatic amines (2-aminopyridine, 4-aminopyridine, 5-aminouracil, sulfadimezine, sulfapyridazine, and L-histidine methyl ester) using the dicyclohexylcarbodiimide method. Amides of GA containing 2-aminopyridine and 5-aminopurine residues had anti-HIV-1 activity in MT-4 cell cultures. The index of selectivity (IS) of the amide of GA with 5-aminouracil was, using various parameters, from 27.73 to 277.32, exceeding values for GA (from 4.45 to 24.0).

Synthesis and anti-HIV activity of triterpene conjugates of α-d-glucosamine

This report describes new triterpene conjugates of α-D-glucosamine, i.e. modified glycyrrhizic acid (GA) analogs containing 18,19-dehydroglycyrrhetic acid 3-O-hemisuccinate and maleate and 11-deoxyglycyrrhetic acid 3-O-hemiphthalate fragments synthesized using N,N′-dicyclohexylcarbodiimide-N-hydroxybenzotriazole. 3-O-[3-(N-2-deoxy-α-D-glucopyranos-2-yl)-carbamoyl]-phthaloyl-11-deoxyglycyrrhetic acid was found to have marked anti-HIV activity (the CD50 (50% cytotoxic concentration) was 150 µg/ml, the ID50 (50% effective concentration) was 1.5 µg/ml, and the index of selectivity (IS, IC50/ID50) was 100) andwas more active than GA in terms of IS (IS = 9.6).

Transformations of Glycyrrhizic Acid: XV. Synthesis of Triterpene Saponins with Monosaccharide Residues Attached through Ester Bonds

Triterpene saponins, glycoside analogues of glycyrrhizic acid with a modified carbohydrate chain containing monosaccharide residues attached through ester bonds, were synthesized. To this end, peracetylated glycyrrhizic acid or its 30-methyl ester were glycosylated by 2,3,4,6-tetra-O-acetyl-α-D-gluco- or -α-D-galactopyranosyl bromide in dichloroethane in the presence of Ag2CO3. Glycerrhetinic acid saponin with D-Galp residues exhibited a higher antiulcer activity than glycyrrhizic acid in rats at a dose of 25 mg/kg.

Synthesis of Glycyrrhizic Acid from Glycyrram and Pharmaciological Characterization of the Product

Glycyrrhizic acid (I) is an active component of licorice root extract obtained from plants of the Glycyrrhiza glabra L. and Glycyrrhiza uralensis Fisher species. The derivatives of acid I possess a broad spectrum of pharmacological properties, including antiinflammatory, antiulcer, antiallergic, antidote, antiviral, and some other types of activity [1]. Glycyrrhizic acid and its salts were recommended for the treatment of various forms of skin and liver cancer [2, 3] and are successfully used in the form of Stronger Neo-Minophagen C (SNMC) preparation for the therapy of patients with AIDS and hepatitis B [4, 5]. A purified glycoside component enters into the drug Clatraprostin (a veterinary preparation) and is used in the new medicinal forms of nonsteroidal antiinflammatory drugs and some other preparations [6, 7]. Previously [8] we proposed a method of obtaining purified glycyrrhizic acid (84 – 89%) from a commercial dry licorice root extract containing 26 – 28% of glycosides (available from the Urals Licorice Plant). Another commercial raw material that can be used for the synthesis of glycyrrhizic acid is glycyrram – a monoammonium salt of glycyrrhizic acid (available from the Chimkentbiofarm corporation). Glycyrram is an antiinflammatory drug used for the treatment of bronchial asthma, eczemas, and allergic dermatitis [9]. For the synthesis of pure glycyrrhizic acid from a commercial monoammonium salt, Volan and Dumazert [10] recrystallized the commercial product from acetic acid (AcOH) and ethanol, after which the purified glycoside was converted into a tripotassium salt (3K-salt) (II). Finally, salt II was converted into glycyrrhizic acid by acidification with an aqueous H 2 SO 4 solution. I: R = R = H, II: R = R = K, III: R = K, R = H.