Glikopeptid-glycyrrhizic acid with methyl ether glycyl-l-valine, exhibiting anti-aids activity

 

(57) Abstract:

Usage: as a tool with anti-AIDS activity. Entity: product: 3-0-[2-0 - b-D-glucopyranosyloxy)- b-D-glucopyranosyloxy] -(3 b , 20 b )-11,30-dioxo-30-(N-6-aminouracil)-30-norolean-12-ene, the output of the 98.9% BF C46H65N3O17so pl. 261 - 264°C. the Substance is able to inhibit the reproduction of HIV-1 in cell culture. table 1.

The invention relates to new biologically active compound, specifically, to glycopeptide-glycyrrhizic acid with methyl ether glycyl-L-valine: 1-0-[(3 , 20 )-11-oxo-20-oxo-20-(N-glycyl-L-valine methyl ester)-30-norolean-12-EN-3-yl] -2-0-[ -D-6-oxo-6-deoxy - 6-(N-glycyl-L-valine methyl ester)-glyukopiranozil- -D-6-oxo-6-deoxy-6-(N-glycyl-L-valine methyl ester)-gluco - pyranoside formula (I)

exhibiting anti-AIDS activity. The specified connection and its properties are not described in literature.

At the present time all over the world are intensively conducted research to find cures AIDS. Known for more than 50 drugs that suppress the reproduction of human immunodeficiency virus (HIV) in vitro [1]. One of these drugs is glycyrrhizin acid (ha) active ingredient extract from the e content of PM lymphocytes and decrease the amount of viral antigen [5]. The mechanism of the antiviral action of GC remains unidentified. However, SC is ineffective as an inhibitor of HIV replication in chronically infected cells.

The aim of the invention is the search for new compounds in the series of derivatives-glycyrrhizic acid, which has anti-AIDS activity.

This goal is achieved glycopeptide-glycyrrhizic acid of the formula (I) exhibiting anti-AIDS activity.

Pharmacological properties of the compounds I.

Antiviral activity of compound I has been studied in models of primary HIV-1-infected lymphoid cells MT-4. Solution of the drug in DMSO (20 mg/ml 50 mg/ml) were introduced into a suspension of HIV-1-infected cells to final concentrations of 100-1000 µg/ml DMSO to a final concentration of 0.5-2.0% . In preliminary experiments it was shown that DMSO at concentrations of 0.5-2.0% does not block the reproduction of HIV-1. About the inhibition of reproduction of HIV-1 in cells judged to reduce the activity of the reverse transcriptase and reduced accumulation of viral antigen (enzyme-linked immunosorbent assay) in the culture fluid 4 days of culture compared with the control (without addition of drug). In caches (AZT), the mechanism of action associated with the blocking of viral reverse transcriptase and termination of viral DNA synthesis [7], and glycyrrhizinic acid (GK), effectively inhibitory reproduction of HIV-1 in cells. The main disadvantage of AZT is its high toxicity [8]. It is established that the investigated compound (I) inhibits the reproduction of HIV-1 in cell culture at a concentration of from 0.1 to 1.0 mg/ml Antiviral activity of compound (I) is similar to the activity of AZT and-GK (inhibition at 98-99%). In breeding 100 and 250 µg/ml glikopeptid (I) inhibits the replication of HIV-1 more efficiently-Ledger. The compound (I) is less toxic to cell culture than AZT. The decrease in the concentration of the drug leads to a decrease toxic effects on the cell culture.

Glikopeptid (I) is less toxic than AZT. LD50glycopeptide (I) 8000 mg/kg

This compound belongs to the class of low-hazard substances.

Synthesis of glycopeptide (I) conducted dicyclohexylcarbodiimide method of peptide synthesis without prior protection of the Oh-groups of the carbohydrate part of the molecule glycoside. The output of glycopeptide (I) was 49%. Analytically pure product was obtained by recrystallization from a mixture of acetone-copeptin (I), effectively inhibits the reproduction of HIV-1 in vitro (in culture cell MT-4), is less toxic than azidothymidine with anti-AIDS activity similar to the activity of AZT and GK.

P R I m e R 1. The study of anti-AIDS activity.

Antiviral activity presented glycopeptide (I) was studied on the model of primary HIV-1-infected lymphoid cells MT-4. Solution of the drug in DMSO (20 - 50 mg/ml) were introduced into a suspension of HIV-1-infected cells to final concentrations of 100-1000 µg/ml DMSO to a final concentration of 0.5-2.0% . In preliminary experiments it was found that DMSO at concentrations of 0.5-2.0% does not block the reproduction of HIV-1. About the inhibition of reproduction of HIV in the cells judged to reduce the activity of the reverse transcriptase and reduced accumulation of viral antigen (enzyme-linked immunosorbent assay) in the culture fluid 4 days of culture compared with the control (without addition of drug). Were used for comparison one of the most effective for the treatment of AIDS drugs - azidothymidine (AZT), the mechanism of action associated with the blocking of viral reverse transcriptase and termination of viral DNA synthesis, and glycyrrhizinic acid (- the cops. It is established that the investigated compound (I) inhibits the reproduction of HIV-1 in cell culture at concentrations from 0.1 to 1.0 mg/ml of virus activity (anti-HIV) connection I similar to AZT and-GK (inhibition by 98.1 reached 98.9% ). It should be noted that at concentrations of 100 and 250 μg/ml of compound I inhibits the replication of HIV-1 more efficiently-Ledger.

Compound I is less toxic to cell culture than AZT, and the reduction of drug concentration leads to decrease toxic effects on the cell culture. The data given in the table.

P R I m m e R 2. Getting glycopeptide (I).

a) Hydrochloride of the methyl ether glycyl-L-valine-Gly-L-Val (OMe).HCl (1A)

To a suspension of 5 g (28.7 mol) Gly-L-Val (Reanal) in 200 ml of dry methanol are added dropwise 20 ml of distilled chloride tiomila while cooling in an ice bath and stirred for 2 h to dissolve the precipitate, incubated 24 h at room temperature, evaporated the solvent in vacuo at a temperature of 30aboutWith the resulting syrup is treated with dry ether and dried in vacuo to constant weight.

Yield 3.0 g (46.6 per cent).

[ ]D20= -87,5about(C = 0.02; 40% EtOH)

Found, %: C 41,97; N 7,27; N 11,94; Cl 15,42.

C8H16
To a solution of 1.64 g (2 mmol), glycyrrhizic acid (92-95%) in 50 ml dry DMF under cooling in an ice bath was added 1.5 g (7 mmol) of Gly-L-Val (OMe).HCl (1A), 1.4 g (6.5 mmol) of N,N'-dicyclohexylcarbodiimide and dropwise 5 ml of dry pyridine, stirred mixture under cooling for 1 h, incubated at room temperature for 48 h with occasional stirring. The precipitate is filtered off, dicyclohexylamine, the filtrate is poured into 400 ml of cold water, acidified with citric acid, a white precipitate is filtered off, washed with water, dried. Obtain 1.3 g (48.7 percent) of glycopeptide (I), which was recrystallized from a mixture of acetone-hexane. Exit homogeneous by TLC of the product 1.2 g (44.9 percent). R(f) = 0,45 (chloroform-methanol-water= 45 : 10 : 1), 0,33 (chloroform-ethanol = 7 : 1). [ ]D20= +25about(C = 0.03, methanol). so pl. 169-171aboutC.

IR , cm-1: 3600-3200 (HE, NH); 1740 (Sooma), 1660 (C11= O), 1580, 1530 (NH).

UVmaxMeon(lg ) : 249 nm (3,95).

Found, %: C 60,20; 48,21; N 6,44.

WITH66H104N6ABOUT22.

Calculated, %: 59,44; N 7,86; N 6,30.

Glikopeptid-glycyrrhizic acid with methyl ether glycyl-L-valine

< / BR>
where R is Gly - L - Val(OMe),

exhibiting anti-AIDS activity.

 

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