Modified nucleoside 5'-triphosphates as antiviral agents

 

(57) Abstract:

Describes the new modified nucleoside 5'-triphosphates General formula: R"'-P(= O)OH-CXX"-P(= O)OH,-O-P(= O) - OH-CH2-A-B, where B=thymine, adenine, uracil or 5-ethyluracil; And has the formula (I), R'=N or N3, R"=H or R, and R"' together form a double bond; Z=O or CH2; R'=Ph, OAlkyl, Oph, NHPh; X'= X '= Br, F, or X'=H, a X=Br. New connections are antiviral agents, in particular, they are able to inhibit the reproduction of human immunodeficiency virus in the culture of human lymphocytes.

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3 table.

The invention relates to the field of molecular biology and Virology, and more specifically to new compounds, modified by P -, and sugar residues of the nucleoside 5'-triphosphates D - and L-series.

New connections are termination substrates reverse transcriptase of human immunodeficiency virus (HIV) and inhibitors of reproduction of HIV in the culture of human lymphocytes, as well as have the ability to prevent infection of healthy cells. In addition, the claimed compounds are specific inhibitors of hepatitis b virus in the culture of human hepatocytes, viruses of herpes group in various cell cultures, as well as the reverse t the two known various compounds, suppressing the reproduction of the human immunodeficiency virus. The most effective of the known compounds is 3'-azido-3'-deoxythymidine (AZT), which are used in medical practice (Mitsuya, H. et al., Proc. Nat. Acad. Sci. USA, 1985, 82, 7096-7100; Mitsuya h , Broder , S., Proc. Nat. Acad. Sci. USA, 1986, 83, 1911-1915). Molecular mechanism of action of the compounds includes diffusion inside cells, infected with HIV. He further subjected to triphosphorylation and specific blocks DNA synthesis catalyzed by reverse transcriptase of HIV. Similarly, there are other antiviral nucleosides used in medical practice for the treatment of AIDS: 2',3'-dideoxycytidine (Mitsuya h, Broder, S., Proc. Natl. Acad. Sci. USA, 1986, 83, 1911-1915), 2', 3'-dideoxyinosine (ibid), 2',3'-dideoxy-2',3'-didehydrothymidine (Herdewijn P. et al., J. Med. Chem., 1987, 30, 1270-1278; M. Baba et al., Biochem. Biophys. Res. Commun., 1987, 142, 128-134) and 2',3'-dideoxy-3'-thiothymidine (Soudeyns H. et al., Antimicrob. Agents Chemother., 1991, 35, 1386-1390). However, phosphorylation of modified nucleosides cellular enzymes is significantly less effective than the natural nucleosides. The process of transformation of the nucleoside in the body into the corresponding 5'-triphosphate takes about 1.5-2 hours. During this time penetrated into the cells, the virus manages in the form proliferates with unmodified trifosfatnogo part is impossible due to their low stability to the action of enzymes hydrolysis and consequently a low ability to penetrate cells. Thus, the applied drugs, even if they are taken at the time of infection may not protect against HIV infection. As an antiviral drug, it was proposed to use derivatives of 3'-azido-3'-deoxythymidine containing a modified phosphate group on the 5'-position, namely H-phosphonate AZT (N.B. Tarasova, and others, they Say. Biol. , 1989, 23, 6, 1716-1724; U.S. Patent 5043437). However, it was shown that in the body of this connection is mainly exposed to dephosphorylating, becoming AZT (Kuznetsova E. C., and others, they Say. Biol., 1995, 29, 2, 415-420).

The basis of the invention is the creation of new nucleoside 5'-triphosphates, which are resistant to the action of enzymes dephosphorylation, are able to penetrate cells and have the electoral activity in inhibition of DNA biosynthesis, catalyzed by the reverse transcriptase of HIV.

The problem is solved by the fact that according to the invention claimed a new connection - P, modified 2'-deoxynucleoside-5'-triphosphates, of General formula:

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where B=thymine, adenine, uracil or 5-ethyluracil

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R'=H or N3;

R"=H or R' and R" together form a double bond;

Z=O or CH2;

R'=Ph, OAlkyl, OPh, NHPh;

X'=X '=Br, F, or X'=H, a X=Br.

ewu N,N'-carbonyldiimidazole and its subsequent condensation with modified triphosphates.

The structure of the claimed compounds was confirmed by UV, NMR and massspectrometry.

Example 1. 5'-(-Phenylamino-, -dibromodiphenyl--phosphorylmethyl)-5'-methoxymethyl-3'-azido-3'-deoxythymidin. (Compound I, In=Thy, R'=N3, R"=H, Z=O, R'=NHPh, X'=X ' =Br).

To a solution of 0.5 mmol of 3'-azido-2',3'-dideoxy-4'-nortilidine-4'-nonphosphate in 10 ml of DMF was added 162 mg (1 mmol) of N,N'-carbonyldiimidazole, stirred for 2 hours at 20oWith, poured 1 ml of methanol, leave it for 30 min and evaporated to dryness, the residue is added 1 mmol of phenylamide dibromochloropropane istributional salt, stirred for 3 h and at 20oWith, poured 200 ml of water and applied to a column (202,5 cm) with Toyopeari DEAE (NBO3-). The elution carried out with a linear gradient of buffer NH4HCO3, pH 7.5 (0->0.4 M, the total volume of 600 ml) with UV control. Fractions with substance lyophilized, the residue is dissolved in 1 ml of water and applied to a column (201,5 cm) with LichroPrep RP18. The elution is conducted with water and UV control. The solution containing the substance, lyophilized, exit 0.26 mmol, 52%. UV-spectrum (in water)max266 nm (9600),1H-NMR-spectrum (D2O , M. D.): 7.64 m (2H, Ph), 7.32 m (3H, arom), 7.60 s (1H, H-6); 6.30 m (1H, H-1'); 5.52 s (1-H, H-4'); 4.46 m (1-H, H-3'); 3.64 d (2H, jCH,P=8.5 Hz ); 2,44 m (1H, H-2'); 1.92 s (3H, CH3-= 13,85 Hz), 0.10 m (-P) FAB-mass m/z: 735 (M++M), 752 (M++H+NH3)

Primer.5'-(-Methyl-, -dibromodiphenyl--phosphorylmethyl)-5'-methoxymethyl-3'-azido-3'-deoxythymidin. (Compound 2, B=Thy, R'=N3, R"=H, Z=O, R'=OMe, X'=X ' =Br).

Synthesis is carried out according to the method of example 1 starting from 5'-phosphonomethyl-5'-methoxymethyl-3'-azido-3'-deoxythymidine and bis(tributylammonium) salt methyl ester dibromochloropropane acid. Exit 0.34 mmol, 68%. UV-spectrum (in water)max268 nm (9600), 1H-NMR-spectrum (D2O , M. D.): 7.60 m (1H, H-6); 6.30 m (1H, H-1'); 5.60 m (1-H, H-4'); 4.38 m (1H, H-3'); 3.64 (2H, JCH,P= 8.5 Hz ); 3.36 (3H, OMe); 2.39 m (1H, H-3'); 1.92 (3H, Me). 31P NMR spectrum (D2O , M. D.): 10,87 d (-P, J-= 35,0 Hz), 8,46 d (-P, J-= 14,95 Hz), -0,12 m (-P). FAB-mass m/z 679 (M++1).

Example 3.5'-(a-Phenyl-, -dibromodiphenyl--phosphorylmethyl)-5'-methoxymethyl-3'-azido-3'-deoxythymidine (Compound 3, B=Thy, R'=H, R"=H, Z= O, R'=OPh, X'=X ' =Br).

Synthesis is carried out according to the method of example 1 starting from 5'-phosphonomethyl-5'-methoxymethyl-3'-azido-3'-deoxythymidine and bis(tributylammonium) salts of phenyl ether dibromochloropropane acid. Exit 0.34 mmol, 68%. UV-spectrum (in water)max268 nm (9600), 1H-NMR-spectrum (D2O , M. D.): 7.68 m (2H, Ph), 7.32 m (3H, Ph), 7.60 (the range (D2O , M. D.): 11,67 d (-P, J-= 33,56 Hz), 8,43 d (-P, J-= 14,08 Hz), 0.05 m (-P) FAB-mass m/z: 741 (M++M), 758 (M++H+NH3).

Primer.5'-(a-Phenyl-, -dibromodiphenyl--phosphorylmethyl)-5'-methoxymethyl-3'-azido-2', 3'-dideoxyuridine (Compound 4, B=Ura, R'=N3, R"= H, Z=O, R'=OPh, X'=X ' =Br).

Synthesis is carried out according to the method of example 1 starting from 5'-phosphonomethyl-5'-methoxymethyl-3'-azido-2', 3'-dideoxyuridine and bis(tributylammonium) salts of phenyl ether dibromochloropropane acid. Exit 0.34 mmol, 68%. UV-spectrum (in water)max268 nm (9600), 1H-NMR-spectrum (D2O , M. D.): 7.60 (1H, J= 8 Hz, H-6); 7.68 m (2H, arom); 7.32 (m, 3H, Ph); 6.22 m (1H, H-1'); 5.80 (1H, J=8 Hz, H-5); 5.28 m (1H, H-4'); 4.50 m (1-H, H-3'); 3.64 (2H, jCH,P= 8.5 Hz ); 2.22 m (1H, H-2');.31P NMR spectrum (D2O , M. D.): 9,24 d (-P, J-= 30,19 Hz), 8,86 d (-P, J-= 13,87 Hz), 0,23 m (-P) FAB-mass m/z: 728 (M++H).

Primer.5'-(a-Phenyl-, -dibromodiphenyl--phosphorylmethyl)-5'-methoxymethyl-3'-azido-2',3'-dideoxy-5-amiloride (Connection 5=5-ethyluracil, R'=N3, R"=H, Z=O, R'=OPh, X'=X ' =Br).

Synthesis is carried out according to the method of example 1 starting from 5'-phosphonomethyl-5'-methoxymethyl-3'-azido-2', 3'-dideoxy-5-utiliarian and bis-(tributyl-ammonium) salt of phenyl ether dibromochloropropane sour 7.32 m (3H, Ph), 6.23 m (1H, H-1'); 5.68 (1H, J=7.5 Hz, H-5); 5.50 m (1-H, H-4') 4.46 m (1-H, H-3'); 2.55 (2H, CH2-CH3), 2.42 m (1H, H-2'), 1.37 m (3H, CH2-CH3).31P NMR spectrum (D2O , M. D.): 12,34 d (-P, J-= 36,5 Hz), 9,13 d (-P, J-= 14,15 Hz), 0.05 m (-P) FAB-mass m/z: 749 (M++H).

Primer.5'-(a-Phenyl-, -dibromodiphenyl--phosphorylmethyl)-5'-methoxymethyl-2', 3'-dideoxyadenosine (Compound 6, B= Ade, R'=R"=H, Z=O, R'=PhO, X'=X ' =Br).

Synthesis is carried out according to the method of example 1 from N-protected 5'-phosphonomethyl-5'-methoxymethyl-2', 3'-dideoxyadenosine and bis(tributyl-Monino) salts of phenyl ether dibromochloropropane acid. The output of 0.32 mmol, 64%. UV-spectrum (in water)max260 nm (15000), 1H-NMR-spectrum (D2O , M. D.): 8.30 (1H, H-2); 8.09 (1H, H-8); 7.68 m (2H, arom), 7.32 m (3H, Ph), 6.33 m (1H, H-1'); are 5.36 m (1H, H-4'); 3.56 (2H, J=9,0 Hz, CH2-P), 2,6-2,3 (4H, H-3', H-2').31P NMR spectrum (D2Oh , M. D.): 11,82 d (-P, J-= 34,5 Hz), 8.59 d (-P, J-= 13,90 Hz), -0.11 m (-P) FAB-mass m/z: 707 (M++N), 724 (M++H+NH3).

Primer.5'-(a-Phenyl-, -deformational--phosphorylmethyl)-5'-methoxymethyl-2',3'-dideoxythymidine (Compound 7, B=Thy, R'=R"=H, Z=O, R'= PhO, X'=X"=F).

Synthesis is carried out according to the method of example 1 starting from 5'-phosphonomethyl-5'-methoxymethyl-2', 3'-dideoxythymidine the KTR (water)max268 nm (9600).1H-NMR-spectrum (D2O , M. D.): 7.62 m (2H, arom), 7.56 m (1H, H-6),

7.32 m (3H, Ph), 6.04 tons (1H, J=6.5 Hz, H-1'); 6.24 m (1-H, H-1'); 5.18 m (1H, H-4'); 3.64 (2H, J=9,0 Hz, CH2-P), 2.6-2.2 m (4H, H-3', H-2'); 1.98 (3H, a ).31P NMR spectrum (D2O , M. D.): 12,08 d (-P, J-= 34,5 Hz), 6,26 d (-P, J-= 13,86 Hz), -1,81 m (-P). FAB-mass m/z: 572 (M++N), 589 (M++H+NH3).

Example 8. 2',3'-Dideoxy-4'-nor-4'-(-phenyl, -dibromodiphenyl--phosphonomethyl-L-Barbadensis (Compound 8, B=Ade, R'=R"=H, Z=CH2, R'=Ph, X'=X ' =Br).

Synthesis is carried out according to the method of example 1. Exit 0.33 mmol, 66%. UV-spectrum (in water) max268 nm (14600),1H NMR spectrum (D2O , M. D.): 8.59 (1H, H-2); 8.30 (1H, H-8); 7.82 m (2H, arom), 7.32 m (3H, Ph), 4.95 t (1H, J=6.5 Hz, H-1'); 3.58 (2H, J=8,5 Hz, CH2-R), 2.8-2.5 m (3H, H-3', H-5); 2.3-2.1 m (2H, H-2'); 1.92 m (1H, H-5).31P-NMR-spectrum (D2O , M. D.): 11.82 d (-P, J-= 32,25 Hz); 0.26 m (-P, Hz); 7.80 d (-P, J-= 15,18 Hz). FAB-mass m/z: 576 (M++H).

Primer.4'-(-Phenyl-, -dibromodiphenyl--methylenephosphonic)-2',3'-dideoxy-2',3'-didehydro-4'-nor-L-Barbadensis (Compound 9, B=Ade, R' and R" form a double bond, Z=CH2, R"'=OPh, X'=X ' =Br).

Synthesis is carried out according to the method similar to the method of example 1 from 2',3'-dideoxy-2',3'-didehydro-4'-nor-L-Barbadensis-4'---- UB>262 nm (14200).1H NMR spectrum (D2O , M. D.): 8.18 (1H, H-2); 8.16 (1H, H-8); 7.68 m (2H, Ph), 7.32 m (3H, Ph), 6.13 m (1-H, H-3'); 5.92 m (1H, H-2'); 5.39 m (1H, H-1'); 4.66 (1H, H-4'); 3.61 (2H, J=9.0 Hz, CH2-R), 2.92 m(1H, H-5); 1.96 m (1H, H-5).31P NMR spectrum (D2O , M. D. ): 11.6 d (-P, J-= 35,10 Hz); 0.29 m (-P); 10.7 d (-P, J-= 16,3 Hz) FAB-mass m/z: 582 (M++H).

Example 10. 2',3'-Dideoxy-2',3'-didehydro-4'-(phenylamino-, -debtor-methylenediphosphonic--methylenephosphonic)-4'-noncarbohydrate (Compound 10, B= Ade, R' and R" form a double bond, Z=CH2, R"'=NHPh, X'=X"=F).

Synthesis is carried out according to the method similar to example 1, from 2',3'-dideoxy-2',3'-didehydro-4'-noncarbohydrate-4'--methylenephosphonate and deformalisation istributional salt. Yield 26%.

UV-spectrum (in water)max260 nm (14100).1H NMR spectrum (D2O , M. D.): 8.18 (1H, H-2); 8.16 (1H, H-8); 7.68 m (2H, Ph), 7.32 m (3H, Ph), 6.24 m (1-H, H-3'); 5.99 m (1H, H-2'); 5.46 m (1H, H-1'); 4.66 (1H, H-4'); 3.74 (2H, JCH,P=8.5 Hz ), 2.86 i (1H, H-5); 1.90 m (1H, H-5).31P-NMR-spectrum (D2O , M. D.): 12,97 d (-P, J-= 33,5 Hz), 6,80 d (-P, J-= 13,32 Hz), -0,71 m (-P) FAB-mass m/z: 598 (M++H).

Primer.2',3'-Dideoxy-4'(-phenyl-, -bromomethylbiphenyl--methylene-phosphonyl)-4'-nortilidine (Compound 11, B=Thy, R'=R"=H, Z=O, R'=PhO, X'= H, X=Br).

Synthesis is carried out Poole feniltiosemicarbazonele. The output of 0.16 mmol, 32%. UV-spectrum (in water)max268 nm (9600),1H-NMR-spectrum (D2O , M. D.): 7.68 m (2N, Agam), 7.32 m (3H, Ph), 7.14 (1H, H-6); 6.14 t (1H, J=6.5 Hz, H-1'); 5.56 m (1H, H-4'); 3.57 (2H, jCH,P=8.5 Hz ); 2.7-2.2 m (4H, H-2', H-3'); 1.95 (3H, a ).31P-NMR-spectrum (D2O , M. D.): 11,84 d (-P, J-= 35,0 Hz), 9,13 d (-P, J-= 13,55 Hz), 0.05 m (-P). FAB-mass m/z: 644 (M++N), 661 (M++H+NH3).

Study of the inhibition of DNA biosynthesis of the claimed compounds in catalysis reactions DNA polymerase was performed using a reverse transcriptase of HIV [K. F. 2.7.7.49], as well as end deoxynucleotidyltransferase from calf thymus [K. F. 2.7.7.31] (Amersham), DNA polymerase , and from human placenta. Single-stranded DNA phage MTR was isolated from the culture liquid of the recipient strain E. coli K12XL1. For a DNA polymerase, and reverse transcriptase of HIV used single-stranded DNA phage MMR as template and as primers synthetic 2'-deoxytetranucleotide (structure of the working part of the complex is shown in Fig. 1). Last deoxynucleotidyltransferase used the same primer, but without the matrix.

The primer tetradecanoate were labeled on the 5'-position using (ID act. 1500 CI/mmol, "Radioisotope") under the catalysis of polynucleotide Imereti (reverse transcriptase).

Single-stranded DNA phage MTR (0.5 µm) hybridized with a primer, labeled32P to the 5'-end (0,75 µm) in the following buffer: 10 mm Tris-Hcl (pH of 8.2), 5 mm MgCl2, 40 mm KCl, 1 mm dithiothreitol (in the case of a reverse transcriptase inhibitor), 100 mm cacodylate sodium (pH of 7.2), 10 mm MgCl2, 1 mm CaCl2and 1 mm dithiothreitol (in the case of end deoxynucleotidyltransferase), 10 mm Tris-Hcl (pH 7.4), 6 mm MgCl2and 0.4 mm dithiotreitol (in the case of DNA polymerases a and e), 10 mm Tris-Hcl (pH 8.5), 6 mm MgCl2and 0.4 mm dithiothreitol (in the case of DNA polymerase ).

Study of the inhibitory properties of compounds in a cell-free system with individual enzyme was performed in 6 ál of incubation mixture containing 0.01 µm labeled primer-matrix complex (Fig.1), an investigational compound, the natural 2'-deoxynucleoside-5'-triphosphates and enzyme (1 unit act. DNA polymerase , and 2 units of activity of the reverse transcriptase or 3 units act. end deoxynucleotidyltransferase) in the appropriate buffer (see above). The reaction was started by adding enzyme and held for 20 min at 37oC. To stop the reaction was added 3 μl of deionized formamide containing 20 mm EDTA, 0.1% bromophenol blue and 0.1% of xylenecyanol. Product is using the x-ray film Kodak XRP-5. Counted the radioactivity of the appropriate bands on the gel and determine the concentration of inhibitor giving 50% inhibition of elongation of the chain. Next I calculated the ratio of this concentration to the concentration of the natural substrate. For comparison used a 3'-azido-2', 3'-dideoxythymidine-5'-triphosphate (AZTTP). The results are shown in table 1.

As can be seen from the table. 1, all compounds have high activity in inhibiting DNA synthesis using catalytic reverse transcriptase of HIV, but do not affect DNA synthesis using catalytic DNA polymerase even when concentrations in 25-100 times higher. They are somewhat superior in this respect, a well-known inhibitor of this enzyme AZTTP.

Determination of antiviral activity were performed on cells in mouse fibroblasts infected with a viral construct containing the reverse transcriptase of the virus leukemia mice, Malone (Mo-MLV) (Shevelev L. J. other, Mol.Biol., 1995, 29, N 5, 1114-1123).

The fibroblasts of the rat line Ratl dissipated on 4-hole die Libro (Flow) 1:10. After 2 days cells were infected with virus pSG1 collected with a fresh monolayer of cells packers RAS and diluted with fresh medium in a ratio of 1:10. Issleduemoi the medium was changed for fresh and again after 1 day was fixed, were stained with Xgal and counted the number of colonies, painted in blue color and, therefore, expressing-galactosidase of E. coli encoded by the virus pSG1 (Shevelev L. J. other, Mol. Biol. , 1995, 29, N 5, 1114-1123). The results were expressed in % of the infected cells in the presence of the tested compound compared to the control in the absence of this connection. Each point is the average of 3 parallel measurements in 2 independent experiments. Standard deviations do not exceed 20%. Were used for comparison of azidothymidine (AZT).

Table 2 shows the results of the suppression of the virus, expressed in concentrations of the compounds that suppress the virus by 50 and 90%.

As can be seen from table 2, the antiviral activity of all compounds is comparable to that of azidothymidine (AZT)

The rate of dephosphorylation of the synthesized compounds in the serum of human blood was determined by adding 2.5 ál of 10 mm solutions of all the synthesized compounds to a total of 47.5 μl of 100% fetal human serum. The solutions were incubated at 37oWith and through 2,5, 5, 10, 20, 30, 40, 60, min, 2, 3, 4, 5, 8, 12, hour, 2, 4, 7, and 14 days were added to 50 μl of water and 230 μl of methanol was shaken and left for 30 min at -20oC. the Samples were centrifuged for 10 min at 12000 gradient of methanol from 0 to 35% in 0.05 M KN2RHO4-buffer for 25 min, flow rate 0.5 ml/min were used For comparison of 3'-azido-2',3'-dideoxythymidine-5'-phosphate and natural substrates dTTP and dATP.

Table 3 presents data on the rate of hydrolysis of the claimed compounds in undiluted blood plasma of a person describing their stability under these conditions. In addition, given the retention times of compounds on solid phase in HPLC, reflecting their degree of hydrophobicity.

From table 3 it can be seen that the time of hydrolysis half the number of compounds 1-8 is about 2000 times greater than that of the natural substrate dTTP and dATP, and AZTTP. However, their hydrophobicity, is proportional to retention time at TLC, is significantly increased, which facilitates their diffusion into the cells.

The modified nucleoside 5-triphosphates General formula

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where B=thymine, adenine, uracil or 5-ethyluracil;

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R' - N or N3;

R" is H or R' and R" together form a double bond;

Z is O or CH2;

R'=Ph, Olkyl, OPh, NHPh;

X'=X '=Br, F, or X'=H, a X=Br

as antiviral agents.

 

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