Glikopeptid-glycyrrhizic acid with debutalbum ester of l-glutamic acid, exhibiting anti-aids activity

 

(57) Abstract:

Usage: as a tool with anti-AIDS activity. Essence: isproduct 3-0-[2-0-(N - b-D-glucopyranosyloxy-L-glutamic acid disutility ether)-N - b-D-glucopyranosyloxy-L-glutamic acid disutility ether]-(3 b , 20 b )-11,30-dioxo-30-(N-L-glutamic acid disutility ether)-30-norolean-12-ene BF C81H131N3O25, yield 64%, Rf= 0,5( CH3Cl : CH3OH : H2O= 45 : 10 : 1). []2D0= +30°(C = 0,02, CH3OH ). Reagent I: glycyrrhizin acid. Reagent II: disutility ester of L-glutamic acid. Reaction conditions: in a medium dry dioxane in the presence of N-hydroxysuccinimide and N,N-dicyclohexylcarbodiimide with further addition of dry triethylamine and dry dimethylformamide. table 1.

The invention relates to new biologically active compounds, specifically, to glycopeptide-glycyrrhizic acid with debutalbum ester of L-glutamic acid: 3-0-[2-0-(N- -D-glucopyranosyloxy-L-glutamic acid disutility ether)-N-D-glucopyranosyloxy-L-glutamic acid ether disutility]-(3 , 20 )-11,30-dioxo-30-(N-L-glutamic acid disutility ether)-30-norolean-12-ene of the formula (1)

Y is not described.

Currently in 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). Japanese researchers have shown that GL inhibits the reproduction of HIV [2-6]. It is also shown that the introduction of the Ledger in high doses (800-1600 mg/day) to patients with AIDS makes them increase in the content of 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 formula I exhibiting anti-AIDS activity.

Pharmacological properties of these compounds were studied in the Department of cultivation and diagnostics retroviruses NGOs Vector.

Antiviral activity of compound I was studied on the model of PE is enzio HIV-1-infected cells to final concentrations of 250-500 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-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).

As Comparators used purified-glycyrrhizinic acid (0.2% to 0.5%), effective inhibitory reproduction of HIV-1 in cells in vitro, and 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 armirovanie of viral DNA synthesis [7].

The main disadvantage of this drug is its high toxicity [8].

It is established that the compound (I) inhibits the reproduction of HIV-1 in cell culture at concentrations from 0.25 to 0.50 mg/ml (of 99.3-99.5 per cent) (table). The level identified antiviral activity glikopeptid (I) is similar to AZT and the General Ledger. The drug is less toxic compared with AZT, and the reduction of the concentration of the drug in the use-Ledger and glycopeptide (I) in equal concentrations (250 μg/ml) anti-HIV - the activity of compound I was more marked.

LD50 of glycopeptide (I) = 650 (500-845) mg/kg (intraperitoneally) and 7000 mg/kg (intragastric) mouse. This compound belongs to the class of low-hazard substances. The compound (I) is less toxic than azidothymidine, the number of living cells (%) in the case of glycopeptide (I) was 2 times greater than that of AZT. When introduced into the stomach (I) is also less toxic than the original-CC, LD50which is 5000 mg/kg (mouse).

The output of glycopeptide (I) 80%. Analytically pure product was obtained through column chromatography on silica gel by elution with a mixture of solvents chloroform-methanol = 50 : 1 and 25 : 1 (v/v).

Thus, the new metaloxide derivative-glycyrrhizic acid glikopeptid (I) effectively inhibits the reproduction of HIV-1 in vitro (in culture cells (MT-4), is less toxic than azidothymidine similar anti-AIDS activity of AZT and GK.

The invention is demonstrated by the following examples:

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

Antiviral activity of glycopeptide (I) was studied on the model of primary HIV-1-infected lymphoid cells MT-4 (in vitro). Solutions of drugs in DMSO (20 mg/ml 50 mg/ml) was made in ASCII 0.5 to 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-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). As Comparators used 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 armirovanie viral DNA, and glycyrrhizinic acid, effectively inhibitory reproduction of HIV-1 in cells. The experimental results are given in the table.

As can be seen from the table data of the investigated compound I inhibits the reproduction of HIV-1 in cell cultures at the indicated concentrations (98.5-99.5% pure). The level identified antiviral activity derived-GK (I) is similar to AZT and the General Ledger. In the breeding of 250 µg/kg glikopeptid (I) more efficient-Ledger in the same concentration. The compound (I) is less toxic compared with AZT, because the number of living cells significantly ( 2-fold) Uru cells.

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

To a solution of 1.64 g (2 mmol) of purified-glycyrrhizic acid (92-95% ) in 50 ml of dry dioxane at 0aboutWith added 1.2 g (10.4 mmol) of N-hydroxysuccinimide and 1.3 g (6 mmol) N,N'-dicyclohexylcarbodiimide and stirred at this temperature for 2.5-3 hours at room 6-7 hour and leave the mixture overnight at 4-8aboutC. Filtered the precipitation of dicyclohexylamine, to the filtrate after cooling in a bath of ice was added 2.0 g of L-Glu(OBu)2HCl (6.8 mmol) and dropwise a 1.0 (9.8 mmol) of dry triethylamine and 5 ml of dry dimethylformamide, maintain the mixture at room temperature with periodic mixing for 24 hours. The solvent is evaporated in vacuum, the residue is dissolved in methylene chloride (200 ml), washed sequentially with 5% HCl, water, 5% NaHCO3, water and dried over MgSO4. By evaporation of the solvent in vacuo get 2,48 g (80%) of glycopeptide (I), which was chromatographically on a column of silica gel L (100/250, Czechoslovakia), elwira mixture of chloroform-methanol 50 : 1, 25 : 1 and 10 : 1 (v/v). A mixture of 50 : 1 and 25 : 1 wash of 1.59 g (64% ) of analytically pure product (I) in the form of an amorphous substance of a yellowish color. Rf= 0.5 (chloroform-methanol-water = 45 : 10 : 1) (Silufol). []D20= +30o(UB>maxMeOH(lg ): 249 nm (4.09 to).

Found, %: C 60,19; H 8,24; N 2,73.

C81H131N3O25.

Calculated, %: C 60,30; H 8,53; N 2,72.

Soluble in acetone, methanol, tetrahydrofuran, dioxane, alcohol, dimethylformamide.

Glikopeptid - glycyrrhizic acid with debutalbum ester of L-glutamic acid of General formula

< / BR>
where R - L - Glu (OBu)2,

exhibiting anti-AIDS activity.

 

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