[Synthesis and biological activity of 2,3-secotriterpene acid mono- and diamides].

Four types of amide (C3; C28; C3-C28) conjugates based on 2,3-seco-18alphaH-oleanane and 2,3-secolupane mono- and dicarboxylic acids were synthesized. The range of diamide derivatives was supplemented with C3-C3' and C28-C28' dicondensed amides with two A-secotriterpene backbones educed by reacting monocarboxylic A-secoacids with biogenic amino acid lysine. Compounds with inhibitory action against herpes virus reproduction (EC50 8.7 and 4.1 McM) were found among the synthesized mono- and diamide derivatives containing an ethyl-beta-alaninate fragment. It has been ascertained that diamide with ethyl-beta-alaninate fragment combines anti-herpes virus properties and anti-HIV activity (EC50 5.1 McM). For active compounds, the maximum non-toxic concentration (MNTC)/EC50 ratios ranges from 9.7 to 40.8. The synthesized amide conjugates do not exhibit any marked cytotoxic effects against human tumor cell lines rabdomiosarcoma RD TE32, A549 lung carcinoma and melanoma MS.

[Synthesis of dihydroquinopymaric acid conjugates with amino acids].

Synthesis of dihydroquinopymaric acid amides and their 2beta-succinyl and 2beta-phthalyl derivatives containing residues of amino acids was carried out for the first time. Antiviral properties of the compounds synthesized were investigated.

[Synthesis of olean-18(19)-ene derivatives from betulin].

The rare olean-18(19)-ene triterpenoids moradiol and moronic acid were synthesized from betulin, and their antiviral properties were investigated.

[Betulonic amides modified at the ring A by amino acids: synthesis and inhibition of influenza A virus reproduction].

The Beckman rearrangement of carboxy- and alkyloxycarbonylalkylamides of 3-hydroxyiminobetulonic acid led to derivatives of 3a-homo-4-aza-3-oxolup-20(29)-ene and 3,4-seco-2-cyanolupa-4(23),20(29)-diene. An X-ray analysis showed methyl 3-(N-acetoximino)lup-20(29)-enoate is the E-isomer. The compounds synthesized exhibited inhibiting activity toward the reproduction of flu A virus in cell culture.

[New betulin derivatives in combination with rimantadine for inhibition of influenza virus reproduction].

The preliminary studies mainly revealed comparable inhibition activities of 3-oxime of betulonic acid, 3beta-O-acetyl-28-O-hemiphthalate of betulin and 3,28-dioxime of betulin against reproduction of influenza viruses A (H1N1), A (H7N1), A (H3N2) and B, as well as against the strains of influenza virus A (H1N1) with intrinsic resistance to rimantadine and A (H7N1) with acquired resistance to the drug. The level of the activity depended on the system used for the virus reproduction. The highest level was observed under conditions providing higher permissibivity, i.e. in the chick embryo fibroblast cell culture for A (H7N1) and in fragments of chick embryo chorioallantoic membranes (for all the viruses). In the experiments with virus A/FPV/Rostock/34 (H7N1) in the chick embryo fibroblast cell culture the average effective concentrations (EC50) of the triterpene compounds were 10.4-17.5 mcM in comparison to EC50 of rimantadine (0.014 mcM). The use of every of the compounds in combination with rimantadine resulted in a 2-16 times decrease of their EC50 and correction of the concentration-effect relation of rimantadine. However, when rimantadine was used alone within the higher range of the nontoxic concentrations (11.6-57.6 mcM). its antiviral properties were significantly less pronounced. As a result the virus titer difference in comparison to the control within the above range of the rimantadine concentrations increased from < 1 to > 2.35 Ig PPU/ml and the relations of the maximal tolerance concentrations of the compounds to their EC50 increased 1.7-15.9 times.

[Synthesis and antiviral activity of lupane triterpenoids with modified cycle E].

A reductive transformation of the peroxide products of ozonolysis of derivatives of 3beta-O-acetyl-22(17-->28)-abeo-lupa-17(28),20(29)-diene and the subsequent intramolecular ketalization led to a compound with a trioxane fragment. This is a new approach to a skeletal modification of triterpenoid cycle E. An activity of the synthesized compounds was found toward the viruses of type A influenza and herpes simplex.

[Synthesis and antiviral activity of amides and conjugates of betulonic acid with amino acids]. / Sintez i protivovirusnaia aktivnost' amidov i kon''iugatov betulonovoi kisloty s aminokislotami.

Betulonic acid amides with aliphatic and heterocyclic amines and with L-amino acids were synthesized by the acid chloride method. Betulonic acid amide and L-methionine derivatives of betulonic acid and its 3-oxime effectively inhibit the influenza A virus. Betulonic acid octadecylamide is active against the herpes simplex type 1 virus. The conjugate of betulonic acid 3-oxime with L-methionine is also active toward HIV-1. The tested compounds mainly show no activity toward the ECHO6 virus, which is devoid of a coat. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no. 1; see also http://www.maik.ru.

Lupane triterpenes and derivatives with antiviral activity.

Betulin and betulinic acid have been modified at the C-3 and C-28 positions and the antiviral activity of derivatives has been evaluated in vitro. It was found that simple modifications of the parent structure of lupane triterpenes produced highly effective agents against influenza A and herpes simplex type 1 viruses.

Antiviral activity of betulin, betulinic and betulonic acids against some enveloped and non-enveloped viruses.

Antiviral properties of betulin, betulinic and betulonic acids were investigated in cell cultures infected with herpes simplex type I, influenza FPV/Rostock and ECHO 6 viruses. All studied triterpenes were active against herpes simplex virus. Betulin and especially betulinic acid also suppressed ECHO 6 virus reproduction.

[Synthesis and antiviral activity of hydrazides and substituted benzalhydrazides of betulinic acid and its derivatives]. / Sintez i protivovirusnaia aktivnost' gidrazidov i zameshchennykh benzal'gidrazidov betulinovoi kisloty i ee proizvodnykh.

New nitrogen-containing derivatives of betulinic and betulonic acids, hydrazides and N'-benzalhydrazides, were synthesized. Their antiviral activities toward of influenza A virus, herpes simplex type I virus, enterovirus ECHO6, and HIV-1 were studied in vitro. Betulinic acid 3-oxime was found to have the highest activity against the influenza virus. Betulonic acid, betulinic acid 4-chlorobenzalhydrazide, betulonic acid 3-oxime benzalhydrazide, and betulinic acid hydrazide inhibited the replication of herpes simplex type I virus. Betulinic acid hydrazide also showed antiviral activity toward HIV-1. All the derivatives of betulinic acid under study displayed a low antiviral activity toward enterovirus ECHO6.

[Synthesis and antiviral activity of ureides and carbamates of betulinic acid and its derivatives]. / Sintez i protivovirusnaia aktivnost' ureidov i karbamatov betulinovoi kisloty i ee proizvodnykh.

Ureides and carbamates of betulinic acid and its derivatives were prepared in good yields by interaction of betulinic acid, betulonic acid, and betulonic acid 3-oxime with amines, amino acids, and alcohols. Ureides of betulonic acid containing L-Val and L-Met residues were found to be effective against herpes simplex type 1 virus. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2003, vol. 29, no. 6; see also http://www.maik.ru.

Chemical and enzymatic synthesis and antiviral properties of 2'-deoxy-2'-fluoroguanosine.

Chemical and enzymatic methods were employed for the synthesis of the title compound, 2'F-Guo 7. High antiviral activity of 2'F-Guo was established in chick embryo cells infected with influenza virus FPV/Rostock/34 (H7N1) and herpes simplex virus (HSV) type I (1C strain).

[Change in the sensitivity of influenza virus, replicating in the presence of rimantadine, to antiviral agents]. / Izmenenie chuvstvitel'nosti virusa grippa, razmnozhivshegosia v prisutstvii remantadina, k protivovirusnym preparatam.

A variant obtained by a single passage of the initial FPV in the presence of 25 micrograms/ml rimantadine is more resistant to the drug than the parental virus. Sensitivity to rimantadine is higher in a variant obtained similarly by cell culture infection with rimantadine-resistant FPV. Potentiation of the antiviral effect of a combination of ribavirin (12-25 micrograms/ml) and rimantadine (0.1-6 micrograms/ml) is decreased or null if rimantadine dose is increased to 12-25 micrograms/ml; this phenomenon does not depend on the sensitivity of infective virus to rimantadine. Antiviral effect of drug combination with a high concentration of rimantadine is due to ribavirin alone.

[Polypeptides from influenza virus, obtained in the presence of high concentrations of rimantadine]. / Polipeptidy virusa grippa, poluchennogo v prisutstvii vysokikh kontsentratsii remantadina.

FPV/Rostock obtained in the presence of remantadine (25 micrograms/ml) is studied. This variant of the virus is characterized by a decreased amount of M1-protein. Its buoyant density in urograffin density gradient is 1.20 gamma/cm3 vs. 1.18 and 1.175 g/cm3 for initial FPV and remantadine-resistant FPV, respectively. Purification and concentration decreases the hemagglutinating activity of the virus 5-10 times more intensely than that of initial and remantadine-resistant FPV. On the other hand, the production of virus-specific proteins and intracellular distribution of hemagglutinin in this virus variant were not changed. The changes associated with a decrease of hemagglutinin and M1-protein content in virions are believed to manifest at a later stage preceding virion release from the cell.

[Features of the antiviral effect of carbocyclic compounds depending on their concentration]. / Osobennosti protivovirusnogo deistviia soedinenii karbotsiklicheskogo riada v zavisimosti ot ikh kontsentratsii.

Antiviral agents and new agents possessing antiviral properties and characterized by a carbocyclic (carcass) structure were shown to differ from other, specifically, heterocyclic compounds, by the presence of a range from the maximally effective to maximally tolerable concentrations, the antiviral effect decreasing in this range of concentrations. This feature was observed in cell cultures, chick embryos, and laboratory animals in experiments with different influenza viruses and RS virus.

[Compounds, similar to acyclovir. VIII. Synthesis and antiviral activity of (R/S)-5-hydroxy-4-hydroxymethyl-3-oxapent-2-yl derivatives of nucleic bases]. / Soedineniia, podobnye atsikloviru. VIII. Sintez i protivovirusnaia aktivnost' (R/S)-5-gidroksi-4-gidroksimetil-3-oksapent-2-il'nykh proizvodnykh nucleinovykh osnovanii.

The (R/S)-5-hydroxy-4-hydroxymethyl-3-oxapent-2-yl derivatives of the uracil, thymidine, cytosine, adenine, guanine and 1,2,4-triazol-3-carboxamide were synthesized using 1,3-diacetoxy-2-(1-acetoxy)propane and 1,3-dichloro-2-(1-chlorethoxy)propane as alkylating agents. The guanine derivatives exhibited activity against HSV-1 (chemotherapeutic index 32).

[The suppression of cellular Na+/H+ exchange leads to the inhibition of influenza virus activity]. / Podavlenie kletochnogo Na+/H+-obmena privodit k ingibirovaniiu aktivnoosti virusa grippa.

It was shown that amiloride, orthovanade and uabain induced almost a two-fold decrease in the rate of incubation medium oxidation by the chick embryo fibroblasts due to the Na+/H+ exchange and inhibited by more than 95 per cent the influenza virus activity. The following mechanism for inhibition of the influenza virus multiplication in the cells under the effect of the above mentioned substances was proposed: suppression of the cellular Na+/H+ exchange responsible for the decrease in pH value in the virus-carrying endosomes----prevention of the decrease in the intraendosomal pH value to the critical level----blocking of the acid dependent process of the virus uncoating----inhibition of the influenza infection as a whole.

[Compounds similar to acyclovir. VII. Attempts to construct an anti-herpetic agent (6-hydroxy-2-oxa-4-hexenyl derivatives of nucleic bases]. / Soedineniia, podobnye atsikloviru. VII. Popytka konstruirovaniia protivogerpeticheskogo preparata (6-gidroksi-2-oksa-4-geksenil'nye proizvodnye nukleinovykh osnovanii.

Based on the available data on the acyclovir's mechanism of action we attempted to predict the antiherpetic activity of 6-hydroxy-2-oxahexen-4-yl derivatives of nucleic bases. In terms of this model 9-(6-hydroxy-2-oxahexen-4-yl) guanine might be active. 6-Hydroxy-2-oxahexen-4-yl derivatives of adenine, guanine, cytosine, thymine, uracil, 1,2,4-triazole-3 and 1,2,4-triazole-5-carboxamide have been synthesized and their activity against herpes virus I investigated. The guanine derivative proved to possess rather high activity (chemotherapeutical index 8).

[Compounds, similar to acyclovir V. Synthesis and antiviral activity of carbethoxyalkoxymethyl derivatives of nucleic bases]. / Soedineniia, podobnye atsikloviru V. Sintez i protivovirusnaia aktivnost' karbétoksialkoksimetil'nykh proizvodnykh nukleinovykh osnovanii.

Ethyl esters and amides of carboxymethoxy-, alpha- and beta-carboxyethoxy- and gamma-carboxypropoxymethyl derivatives of adenine, guanine, cytosine, uracil, thymine, 1,2,4-triazole-3- and -5-carboxamide were synthesized and their antiviral activity was studied.

[Change in the influenza virus upon multiplication in the presence of high concentrations of remantadine]. / Izmenenie virusa grippa pri razmnozhenii v prisutstvii vysokikh kontsentratsii remantadine.

It was established that classical fowl plague virus Rostock (H7N1) propagated in culture to which 10-25 micrograms/ml of remantadine had been added differed from the original FPV and its remantadine-resistant variant by markedly reduced infectious and hemagglutinating activity and, to a lesser extent, neuraminidase activity, lower amounts of M protein and hemagglutinin, incomplete cleavage of hemagglutinin, and significant loss of spikes on the virion surface.