Synthesis of Glycyrrhizic Acid Conjugates with S-Benzyl-L-Cysteine and Their Antiviral Activity.

A new method for the synthesis of glycyrrhizic acid (GA) conjugates with S-benzyl-L-cysteine using 1-ethyl-3-(3-dimethylaminoproopyl)carbodiimide is proposed. It is established that 3-O-{2-O-[N-(ß-D-glucopyranosyluronyl)-L-cysteine-S-benzyl]-N-(ß-D-glucopyranosyluronyl)-L-cysteine-S-benzyl}-(3ß,20ß)-11-oxo-30-(N-carbonyl-L-cysteine-S-benzyl)-30-norolean-12-ene is superior to GA in inhibiting the accumulation of HIV-I virus-specific protein p24 (viral antigen) in MT-4 cell culture (IC50 3 µg/mL, SI 90) and is 50 - 55 times less toxic to cells than azidothymidine.

Synthesis and Anti-HIV-1 Activity of Olean-9(11),12(13)-Dien-30-Oic Acid 3ß-(2-O-ß-D-Glucuronopyranosyl-ß-D-Glucuronopyranoside).

The glycyrrhizic acid (GA) analog olean-9(11),12(13)-dien-30-oic acid 3ß-(2-O-ß-D-glucuronopyranosyl-ß-D-glucuronopyranoside) (II) was synthesized via reduction of GA by NaBH4 in refluxing 2-PrOH:H2O with subsequent work up with HCl (5%). The cytotoxicity and antiviral activity of this glycoside against HIV-1 was studied in MT-4 cell culture. It was found that II was practically non-toxic for MT-4 cells while inhibiting accumulation of virus-specific protein p24 and RNA-dependent DNA-polymerase activity of HIV-1 reverse transcriptase (RT) (IC50 3.1 ±1.0 µg/mL).

Synthesis and anti-HIV-1 activity of new conjugates of 18ß- and 18α-glycyrrhizic acids with aspartic acid esters.

New conjugates of 18ß- and 18α-glycyrrhizic acids (GAs) each containing two di- or α-methyl esters of L-aspartic acid in the carbohydrate part of the glycosides were synthesized by the activated ester method using the N-hydroxysuccinimide (HOSu) and N,N'-dicyclohexylcarbodiimide. It was found that the conjugate of 18ß-GA with Asp(OMe)(OMe) (4) at a concentration of 250 µg/mL inhibited effectively RT of HIV-1 and the accumulation of virus antigen p24 in MT-4 cell culture (95-97 %) and protected cells from the cytopathogenic action of the virus.

Synthesis and antiviral activity of 18α-glycyrrhizic acid and its esters.

New esters (sulfate, nicotinates, and 4-methoxycinnamate) of 18α-glycyrrhizic acid (18α-GA) were synthesized; these were D/E-trans-isomers of natural 18ß-GA (GA), which is the major triterpene glycoside in the roots of Spanish licorice and Urals licorice (Glycyrrhiza glabra L. and Gl. uralensis Fisher). Changes in the stereochemistry of the GA aglycone led to significant decreases in its anti-HIV-1 activity.

[Synthesis and biological activity of new glycyrrhizic acid conjugates with amino acids and dipeptides].

New glycyrrhizic acid (GA) conjugates were synthesized with the use of tert-butyl esters of amino acids or benzyl esters of dipeptides; they contained two residues of L-amino acids (Met, Phe, Pro, and Ile or dipeptides Gly-Leu and Gly-Phe). Activation of GA carboxy groups was carried out with the help of N-hydroxysuccinimide, N,N'-dicyclohexylcarbodiimide, or N-hydroxybenzotriazole with dicyclohexylcarbodiimide. A proline-containing GA derivative is a low-toxic substance; it raises the level of agglutinins by 3.7 times in the blood of mice and 3 times that of hemolysins compared with the control. Dipeptide GA derivatives possess an expressed anti-HIV-1 activity in cultures of MT-4 cells and are 90-70 times less cytotoxic than azidothymidine. The selectivity index of the compounds exceeds those of GA by 110 and 34 times, respectively.

[A simple method of synthesis of triterpene glycosides similar to glycyrrhizic acid and their hepatoprotective activity in vitro].

A simplified method of synthesis of triterpene l,2-trans-glycosides was developed using the glycosylation of glycyrrhetic acid (GLA) and 18,19-dehydro-GLA by beta-pyranose peracetates in the presence of SnCl(4) and molecular sieves 4 A. The synthesized glycosides exhibited hepatoprotective activity toward the human hepatoma HepG2 cell line on the model of alcohol hepatitis and decreased the level of TNF-alpha protein.

Prospects for the creation of new antiviral drugs based on glycyrrhizic acid and its derivatives (a review).

The review is devoted to the problem of creating new antiviral drugs based on glycyrrhizic acid (GA), the major triterpene glycoside extracted from roots of common and Ural licorice (Glycyrrhiza glabra L. and G. uralensis Fisher, respectively). Published data on the natural GA sources, antiviral activity of GA and its derivatives, clinical applications of GA-based drugs, and the properties of GA-containing biologically active nutrient additives are summarized. Possible mechanisms of the antiviral activity of GA and its derivatives are examined. It is shown that chemical modification of GA is a promising way of designing new highly active antiviral drugs for the prophylaxis and treatment of HIV, hepatitis B and C, corona-virus, and herpes simplex virus infections.

[Synthesis and immunomodulating activity of new glycopeptides of glycyrrhizic acid containing residues of L-glutamic acid].

New glycopeptides of glycyrrhizic acid (GA) containing Glu residues and their alpha-methyl esters, gamma-methyl esters, and alpha,gamma-dimethyl esters were synthesized using N,N'-dicyclohexylcarbodiimide in the presence of N-hydroxybenzotriazole or N-hydroxysuccinimide. Formation of amide bonds was observed on all the three COOH groups of GA, or selectively on the COOH groups of the GA carbohydrate part in dependence on the ratio of reagents and the reaction conditions. The GA glycopeptide with three residues of Glu(OH)-OMe at a dose of 2 mg/kg stimulated the production of antibody-forming cells in mouse spleen in comparison with the control. The GA glycopeptide containing Glu residues only in the GA carbohydrate part turned out to be an immunosuppressor. The glycopeptide of the 30-methyl ester of GA with residues of free Glu in its carbohydrate part increased the hemagglutinine titer at oral doses of 2 and 10 mg/kg. All the studied compounds had practically no effect on the delayed-type hypersensitivity in mice.

[The synthesis and antiviral activity of glycyrrhizic acid conjugates with alpha-D-glucosamine and some glycosylamines]. / Sintez kon''iugatov glitsirrizinovoi kisloty s al'fa-D-gliukozaminom i nekotorymi glikozilaminami i ikh protivovirusnaia aktivnost'.

Glycyrrhizic acid and its 30-methyl ester were conjugated with 2-amino-1,3,4,6-tetra-O-acetyl-2-deoxy-alpha-D-glucopyranose, 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl amine, 2,3,4-tri-O-acetyl-apha-L-arabinopyranosyl amine, 2-acetamido-2-deoxy-beta-D-glucopyranosyl amine, and beta-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-beta-D-glucopyranosyl amine in the carbohydrate part of its molecule exhibited antiviral activity (ID50 4 microg/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 microg/ml. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no. 3; see also http://www.maik.ru.

[Synthesis and immunomodulating activity of new diglycopeptides of of glycyrrhizinic acid and it's 30-methyl ester]. / Sintez i immunomoduliruiushchaia aktivnost' novykh diglikopeptidov glitsirrizinovoi kisloty i ee 30-metilovogo éfira.

New amino acid derivatives of glycyrrhizic acid and its methyl ester were selectively synthesized using active N-succinimide esters. The compounds with residues of glycine ethyl ester and alanine methyl and butyl esters increased the level of agglutinins and hemolysins in blood serum of mice two- to threefold in comparison with the control upon parenteral administration at a dose of 2 mg/kg for 14 days. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no. 2; see also http://www.maik.ru.

[Synthesis and immunostimulating activity of cysteine-containing glycopeptide derivatives of glycyrrhizic acid]. / Sintez i immunostimuliruiushchaia aktivnost' tsisteinsoderzhashchikh glikopeptidnykh proizvodnykh glitsirrizinovoi kisloty.

New cysteine-containing derivatives of glycyrrhizic acid were synthesized by its coupling with Cys(Bzl) esters or the Cys(Bzl)-Val-OBu(t) dipeptide by the active ester method (DCC/HOSu) or by Woodward's reagent K. The derivatives with Cys(Bzl) and Cys(Bzl)-Val residues attached to the carbohydrate part of the molecule stimulated the primary immune response and the reaction of delayed-type hypersensitivity in mice at a dose of 2 mg/kg. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no. 1; see also http://www.maik.ru.

[Transformation of glycyrrhizinic acid. XV. Synthesis of triterpene saponins with monosaccharide residues, attached through complex ester bonds]. / Transformatsii glitsirrizinovoi kisloty. XV. Sintez triterpenovykh saponinov s monosakharidnymi ostatkami, prikreplennymi slozhnoéfirnymi sviaziami.

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-alpha-D-gluco-or-alpha-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. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2003, vol. 29, no. 6; see also http://www.maik.ru.

[Prooxidant effect of inflammation mediators]. / K prooksidantnomu deistviiu mediatorov vospaleniia.

The authors studied the effect of inflammation mediators--serotonin, histamine, bradykinin, as well as that of trypsin on lipid peroxidation (LPO). It was demonstrated by chemiluminescence of native hepatic mitochondria in vitro and blood serum in vivo and tests for diene conjugates and malonic dialdehyde that inflammation mediators (histamine, serotonin, bradykinin) and the proteolytic enzyme trypsin activate LPO processes, which correlates with the antiinflammatory effect of these biologically active substances.

[Transformation of glycyrrhizic acid. Synthesis of glycopeptides of glycyrrhizic acid monomethyl ether, having anti-inflammatory and immunostimulating action]. / Transformatsii glitsirrizinovoi kisloty. Sintez glikopeptidov monometilovogo éfira glitsirrizinovoi kisloty, proiavlliaiushchikh protivosvospatitel'noe i immunostimuliruiushchee deistvie.

Three triterpene glycopeptides, glycyrrhizic acid monomethly ester derivatives containing peptide fragment of N-acetylmuramoyldipeptide and its analogues, are synthesized. They possess high prednizolone-like antiinflammatory activity and display pronounced stimulative effect on humoral factors of immunity.