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Biomedical subjects

R Snoeck

Publications and source records attributed to R Snoeck.

At least 91 records · Page 5Linked to original sources
PubMed1997

Polyanion inhibitors of human immunodeficiency virus and other viruses. 6. Micelle-like anti-HIV polyanionic compounds based on a carbohydrate core.

A new class of polyanionic compounds, inhibitors of human immunodeficiency virus, was obtained from radical addition of mercapto acid or mercapto ester on a perallylated carbohydrate under UV irradiation with a catalytic amount of AIBN. Unlike the polyanions that we have previously prepared by polymerization reactions, the compounds are structurally well defined. Polyanions bearing 16 carboxylate groups showed a 50% inhibitory concentration (IC50) of 0.1-4.1 micrograms/mL against HIV-1 in MT-4 cells while not being toxic to the host cells at concentrations up to 125 micrograms/mL. The most potent polyanions also proved active against human cytomegalovirus at concentrations of 1-14 micrograms/mL. No activity was observed against any of the other viruses tested (i.e., herpes simplex virus, vesicular stomatitis virus, Sindbis, Semliki forest, parainfluenza-3, Junin, Tacaribe, Coxsackie B4, polio-1, reo-1, or vaccinia virus).

Anti-HIV Agents↗
PubMed1997

Polyanion inhibitors of human immunodeficiency virus and other viruses. 5. Telomerized anionic surfactants derived from amino acids.

omega-Acryloyl anionic surfactants, whose polar heads are derived from amino acids, have been telomerized to prepare polyanions of a predetermined molecular weight. The main goal of this study was to verify whether the antiviral activity is influenced by the degree of polymerization of the polyanions. The oligomeric polyanions were evaluated for their activity against human immunodeficiency virus (HIV-1 or HIV-2) and various other RNA and DNA viruses. With regard to their anti-HIV activity, a minimum number of anionic groups was necessary to achieve an inhibitory effect. Moreover, to be active the overall conformation of the polyanion must be such that the anionic groups are located on the external site of the molecule. With some of the polyanions, a 50% inhibition concentration (IC50) as low as 1 microgram/ mL, or even 0.1 microgram/mL, was noted against HIV-1 in CEM-4 and MT-4 cells, respectively. The most potent polyanions also proved active against human cytomegalovirus and herpex simplex virus at concentrations of 5-10 and 20-40 micrograms/mL, respectively. No activity was observed against any of the other viruses tested (i.e., vesicular stomatitis, Sindbis, Semliki forest, parainfluenza, Junin, Tacaribe, Coxsackie, polio, reo, and vaccinia). No toxicity for the host cells was observed at concentrations up to 200 micrograms/mL.

Amino Acids↗
PubMed1997

Novel carbocyclic nucleosides containing a cyclopentyl ring. Adenosine and uridine analogues.

cis-3-Aminomethylcyclopentylmethanol (4) was used as a precursor in the synthesis of carbocyclic nucleosides containing adenine, hypoxanthine, 8-azahypoxanthine, uracil, and 5-iodouracil bases. None of these compounds had appreciable activity against eighteen viruses in the concentration ranges tested. Two of them showed a weak cytostatic activity against three tumor lines.

Adenosine↗
PubMed1997

Activities of various compounds against murine and primate polyomaviruses.

Polyomavirus infections in humans are due to BK virus (BKV) and JC virus (JCV). Diseases associated with human polyomaviruses occur mostly in immunocompromised adults, e.g., progressive multifocal leukoencephalopathy (PML), caused by JCV, in AIDS patients and hemorrhagic cystitis and uretral stenosis, caused by BKV, in transplant recipients. No therapy is available for these diseases, which necessitates the development of chemical entities that are active against polyomaviruses. Several antiviral compounds were evaluated to determine their effects on the in vitro replication of mouse polyomavirus and the primate viruses simian virus 40 (SV40), SV40 PML-1, and SV40 PML-2. The activity of the different compounds was assessed by a cytopathic effect reduction assay and confirmed in a virus yield assay. Cidofovir [HPMPC; (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine] and its cyclic counterpart emerged as the most selective antipolyomavirus agents. The 50% inhibitory concentrations for HPMPC were in the range of 4 to 7 micrograms/ml, and its selectivity index varied from 11 to 20 for mouse polyomavirus and from 23 to 33 for SV40 strains in confluent cell monolayers. Cell cytotoxicity was up to 15-fold greater in growing cells. Other acyclic nucleoside phosphonates (i.e., HPMPA; [(S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine] and PMEG [9-(2-phosphonylmethoxyethyl)-guanine]) also showed some activity but had low selectivity. None of the other drugs tested against these animal viruses (i.e., acyclovir, ganciclovir, brivudine, ribavirin, foscarnet, and cytarabine) showed significant activity. Thus, HPMPC deserves further evaluation as a candidate drug for polyomavirus infections in the immunocompromised host.

Animals↗
PubMed1997

New neplanocin analogues. VIII. Synthesis and biological activity of 6'-C-ethyl, -ethenyl, and -ethynyl derivatives of neplanocin A.

This report describes the synthesis and antiviral effects of (6'R)-6'-C-ethynyl, -ethenyl, and -ethyl derivatives of neplanocin A (7a, 8a, and 9a, respectively) and the corresponding 6'S-diastereomers (7b, 8b, and 9b, respectively), as examples of 6'-C-substituted analogues of neplanocin A. Grignard reaction of the 6'-formyl derivative 4, which was readily prepared from neplanocin A, with ethynylmagnesium bromide gave a diastereomeric mixture of the corresponding 1,2-addition products 5a and 5b. After removal of the protecting groups, (6'R)- and (6'S)-6'-C-ethynylneplanocin A's (7a, 7b) were separated. The corresponding ethenyl derivatives 8a and 8b and ethyl derivatives 9a and 9b were prepared by catalytic hydrogenation of 7a and 7b, respectively. As compared to neplanocin A, the new neplanocin A derivatives were much weaker inhibitors of S-adenosyl-L-homocysteine hydrolase, the R-diastereomers being more inhibitory than the S-diastereomers. The decreasing order of activity was 7a > 8a > 7b > 9a > 8b > 9b. The cytotoxicity (for CEM cells) followed exactly the same order. Of these compounds, (6'R)-6'-C-ethynylneplanocin A (7a, RENPA) showed an antiviral activity spectrum that was comparable to, and an antiviral specificity that was higher than, that of neplanocin A. RENPA was particularly active against those viruses (i.e. vaccinia virus, vesicular stomatitis virus) that are known to be highly sensitive to AdoHcy hydrolase inhibitors.

Adenosine↗
PubMed1996

New neplanocin analogues. 7. Synthesis and antiviral activity of 2-halo derivatives of neplanocin A.

The syntheses and the antiviral activities of 2-halo derivatives of neplanocin A (1b,c), (6'R)-6'-C-methylneplanocin A (2b), and dehydroxymethylneplanocin A (3b,c) are described. SN2 reaction of the known cyclopentenyl units 12 and 13 with 2-haloadenines under basic conditions gave the protected carbocyclic nucleosides 14b,c and 15b,c, respectively. Starting from the cyclopentenone derivative 5, the optically active tosyloxycyclopentene derivative 11 was prepared, which was similarly condensed with 2-fluoroadenine to give the protected (6'R)-6'-C-methyl derivative 16b. Deprotection of these compounds afforded the target 2-halo derivatives of neplanocin A. Of these new compounds, 2-fluoroneplanocin A (1b) showed an antiviral potency and a spectrum that was comparable to that of neplanocin A (1a). It was particularly active against vaccinia virus, vesicular stomatitis virus, parainfluenza virus, reovirus, arenaviruses (Junin, Tacaribe), and human cytomegalovirus, i.e., those viruses that fall within the purview of the S-adenosyl-L-homocysteine hydrolase inhibitors.

Adenosine↗
PubMed1996

Synthesis and antiviral activity evaluation of some new aminoadamantane derivatives. 2.

The synthesis of some new aminoadamantane derivatives is described. The new compounds were evaluated against a wide range of viruses [influenza A H1N1, influenza A H2N2, influenza A H3N2, influenza B, parainfluenza 3, herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), thymidine kinase-deficient (TK-) HSV-1, vaccinia, vesicular stomatitis, polio 1, Coxsackie B4, Sindbis, Semliki forest, Reo 1, varicella-zoster virus (VZV), TK- VZV, human cytomegalovirus (HCMV), and human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2)]. Some of them proved markedly active against the influenza A H2N2 (compounds 4a,b, 5a, 6a, and 7a), H3N2 (compounds 5a, 6a, and 7a), and H1N1 (compounds 4b,c and 6d). Since compounds 5a, 6a, and 7a, amantadine, and rimantadine showed the same comparative pattern of potency against influenza strains H2N2, H3N2, and B, it may postulated that they act according to a similar mechanism, with regard to their "amine" effect, on the M2 ion channel of influenza A (H1N1, H2N2, or H3N2). In general, no significant activity was noted with any of the new compounds against any of the other viruses tested, making their activity against influenza virus more specific and striking. Borderline activity was noted with some of the compounds (4b,c, 5a-c, and 8a) against HIV-1.

Adamantane↗
PubMed1996

Synthesis of 2'-aminomethyl derivatives of N-(2-(phosphonomethoxy)ethyl) nucleotide analogues as potential antiviral agents.

A series of purine and pyrimidine N-(2-(phosphonomethoxy)ethyl) derivatives bearing aminomethyl, (dimethylamino)methyl, morpholinomethyl, and (trimethylammonio)methyl groups at the 2'-position were synthesized. The compounds were prepared by alkylation of the heterocyclic bases with appropriately substituted (aminoalkyl)oxiranes followed by condensation of the resulting intermediates with dialkyl ((p-tolylsulfonyl)oxy)methanephosphonate and subsequent treatment of the obtained diester with bromotrimethylsilane. 9-(3-Amino-2-(phosphonomethoxy)propyl)adenine (2a) proved active against varicella zoster virus (VZV), cytomegalovirus (CMV), and Moloney murine sarcoma virus (MSV) in the concentration range of 7-35 micrograms/mL. None of the other aminoalkyl derivatives demonstrated significant antiviral activity against herpes simplex virus type 1 and 2 (HSV-1 and HSV-2), VZV, (CMV), vaccinia virus (VV), MSV, and human immunodeficiency virus type 1 and 2 (HIV-1 and HIV-2).

3T3 Cells↗
PubMed1996

New neplanocin analogues. 6. Synthesis and potent antiviral activity of 6'-homoneplanocin A1.

The design, synthesis, and antiviral activities of 6'-homoneplanocin A (HNPA, 3) and its congeners having nucleobases other than adenine, such as 3-deazaadenine (4), guanine (5), thymine (6), and cytosine (7), were described. Starting from the known cyclopentenone derivative 8, the optically active (mesyloxy)cyclopentene derivative 15 was prepared, which was condensed with nucleobases then deprotected to give target compounds 3-7. Of these compounds, HNPA showed an antiviral activity spectrum that was comparable to, and an antiviral specificity that was higher than, that of neplanocin A. HNPA proved particularly active against human cytomegalovirus, vaccinia virus, parainfluenza virus, vesicular stomatitis virus, and arenaviruses, which is compatible with an antiviral action targeted at S-adenosylhomocysteine hydrolase. HNPA appears to be a promising candidate drug for the treatment of these viruses.

Adenosine↗
PubMed1996

Polyanion inhibitors of human immunodeficiency virus and other viruses. Part 2. Polymerized anionic surfactants derived from amino acids and dipeptides.

A series of new polyanions was synthesized via gamma-polymerization, in aqueous micellar solution, of omega-unsaturated anionic surfactants whose polar head was derived from amino acids or dipeptides. The obtained polyanions were evaluated for their activity against human immunodeficiency virus (HIV-1, HIV-2) and various other RNA and DNA viruses. All the test compounds proved active against HIV-1 and HIV-2, their 50% inhibitory concentration (IC50) being in the range of 0.04-7.5 micrograms/mL, while they were not toxic to the host cells (CEM-4 or MT-4) at concentrations up to 100 micrograms/mL or higher. The HIV-inhibitory effect increased with the hydrophilic character of the amino acid moiety. The compounds were found to interact with both the viral envelope glycoprotein gp120 and the cellular CD4 receptor, thus blocking virus-cell binding and virus-induced syncytium formation. These polyanions also proved active against human cytomegalovirus at about the same IC50 as for HIV. In addition, they were also active, albeit at somewhat higher IC50 values (0.8-20 micrograms/mL), against other enveloped viruses such as respiratory syncytial virus and arenaviruses (Junin and Tacaribe). At yet higher IC50 values ( > or = 20 micrograms/mL), some of the compounds showed activity against influenza A virus. No activity was observed with any of the compounds against vesicular stomatitis virus, Sindbis virus, Semliki forest virus, influenza B, parainfluenza type 3, and the nonenveloped viruses Coxsackie type B4, polio type 1, and reovirus type 1.

Animals↗
PubMed1996

Human cytomegalovirus increases constitutive production of interleukin-6 and leukemia inhibitory factor by bone marrow stromal cells.

Human cytomegalovirus (CMV) infection is often associated with myelosuppression and acute inflammatory reaction in immunocompromised patients. We have previously documented that CMV exposure of bone marrow (BM) stromal cells reduces the capacity of these cells to support hematopoiesis because of a decreased production of colony-stimulating factors. This study examines the potential role of CMV on constitutive and lipopolysaccharide (LPS)-stimulated production of cytokines involved in inflammatory reaction, interleukin-6 (IL-6) and leukemia inhibitory factor (LIF) by BM stromal cells. The release of IL-6 was already detectable 2 hours post CMV-infection (2.5-fold increase in production) and the cumulative production of IL-6 after 5 days of infection was 23 +/- 1.2 ng/mL (ninefold increase in production). CMV was also able to induce a time-dependent production of LIF that was maximal 8 hours after CMV infection (2.5-fold increase in production). Concomitantly, there was no detectable release of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage CSF (GM-CSF) by CMV-infected stromal cells. The similar IL-6 and LIF production in the presence of polymyxin B ruled out the possibility that this increase could be caused by contamination of the viral stock by endotoxin. In addition, ultraviolet-inactivated virus behaved similarly to live virus and caused the release of IL-6 and LIF. However, heat-inactivated CMV was unable to induce IL-6 and LIF secretion by BM stromal cells. The production of IL-6 and LIF was also evaluated after stimulation by LPS. After 5 days of CMV exposure, the LPS-stimulated production of IL-6 and LIF was significantly lower than uninfected controls. This LPS-induced release of cytokine production was found to be dependent of viral replication. The experiments have shown that CMV is a potent inducer of IL-6 and LIF with differential effect on constitutive and LPS-stimulated cytokine production by stromal cells; we suggest that CMV induction of IL-6 and LIF during the first hours of infection could play a role in CMV-induced inflammatory reaction. Moreover, our results show that human CMV can disturb the balanced cytokine network involved in the regulation of hematopoiesis.

Bone Marrow Cells↗
PubMed1996

Patterns of resistance and sensitivity to antiviral compounds of drug-resistant strains of human cytomegalovirus selected in vitro.

Drug-resistant human cytomegalovirus (HCMV) strains were selected in human embryonic lung (HEL) fibroblasts under pressure of the (S)-3-hydroxy-2-phosphonylmethoxypropyl (HPMP) derivatives of cytosine (HPMPC) and adenine (HPMPA), the 2-phosphonylmethoxyethyl (PME) derivative of 2,6-diaminopurine (PMEDAP), ganciclovir (GCV), acyclovir (ACV), and foscarnet (PFA). Drug susceptibility profiles of the different drug-resistant (i.e., GCVr, HPMPCr, HPMPAr, PFAr, ACVr, and PMEDAPr) strains were determined in HEL cells. A considerable degree of cross-resistance against GCV, HPMPC, and HPMPA occurred with GCVr, HPMPCr, and HPMPAr strains. No changes in susceptibility to 9-(2-phosphonylmethoxyethyl)adenine (PMEA), PMEDAP, ACV, or PFA were detected for the HPMPCr, HPMPAr, and GCVr strains when compared to the wild-type virus. On the other hand, a significant degree of cross-resistance was noted with the PMEDAPr, PFAr, and ACVr strains against PMEA, PMEDAP, PFA, and ACV. NO differences in susceptibility to HPMPC, HPMPA and GCV were observed for the ACVr, PFAr, and PMEDAPr strains relative to the wild type. The drug susceptibility profiles of the different resistant strains point to a common mechanism of HCMV resistance to PFA and the PME derivatives that is different from the mechanism of HCMV resistance to the HPMP derivatives.

Acyclovir↗
PubMed1996

Imbalance in production of cytokines by bone marrow stromal cells following cytomegalovirus infection.

The effect of cytomegalovirus (CMV) infection on the production of growth factors and negative regulators in unstimulated or lipopolysaccharide-stimulated human bone marrow stromal cells was assessed. After 5 days, the constitutive and lipopolysaccharide-stimulated production of growth factors was significantly decreased in CMV-infected compared with uninfected stromal cells. This decrease was noted as early as 72 h after infection and appeared to be strictly related to viral replication. On the other hand, the production of inhibitory factors was increased after CMV infection, and this increased release was detectable as early as 24 h after infection. No modulation in the production of interleukin-10 was observed after CMV infection. These data suggest that CMV disturbs the balanced cytokine network, which controls proliferation and differentiation of hematopoietic progenitors. CMV-induced myelosuppression results from this lack of production of growth factors and excess production of inhibitory factors.

Bone Marrow Cells↗
PubMed1996

Synthesis and antiviral activity of 6-chloropurine arabinoside and its 2'-deoxy-2'-fluoro derivative.

6-Chloropurine arabinoside (3a) was obtained by treatment of the 2'-O-acetylated congener (2) with ammonia in methanol. The 3',5'-di-O-tritylated riboside (6) was allowed to react with diethylaminosulfur trifluoride (DAST) in the presence of pyridine to give the 2'-deoxy-2'-fluoroarabinoside (7), from which 6-chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)purine (3b) was obtained. The antiviral effects of 3a and 3b were assayed against several DNA and RNA viruses. Only 3a displayed potent activity against varicella-zoster virus (VZV). This antiviral activity was dependent on phosphorylation by the VZV-induced thymidine kinase (TK). Compound 3a showed moderate activity against other DNA viruses, herpes simplex type 1 (HSV-1) and type 2 (HSV-2), and vaccinia virus. They were equally active against TK- and TK+ strains of HSV-1, which suggests that the HSV-1-encoded TK does not play a role in the anti-HSV-1 activity. No activity was noted with any of the compounds against various RNA viruses, including human immunodeficiency virus, at subtoxic concentrations.

Antiviral Agents↗
PubMed1995

Polyanion inhibitors of human immunodeficiency virus and other viruses. 1. Polymerized anionic surfactants.

A series of polyanionic compounds was synthesized and evaluated for their activity against human immunodeficiency virus (HIV-1, HIV-2) and various other RNA and DNA viruses. Several compounds, i.e., 2p, 3p, 8p, 13p, 14p, 15p, 17p, 18p, and 19p, proved active against HIV-1 within the concentration range of 0.1-3 micrograms/mL while not being toxic to the host cells (CEM, MT-4) at concentrations up to 100 micrograms/mL or higher. As a rule, these polyanionic compounds proved also active, albeit at somewhat higher concentrations than those required for HIV-1 inhibition, against a number of other enveloped viruses, including HIV-2, human cytomegalovirus, influenza A virus, respiratory syncytial virus, and arenaviruses (Junin and Tacaribe). Among the most potent HIV-1 inhibitors ranked compounds 18p and 19p, the sodium salts of N-methylamides obtained by polymerization of monomers prepared starting from 10-undecenoyl chloride and omega-aminoalkanoic acids.

Antiviral Agents↗
PubMed1995

3-deaza- and 7-deaza-5'-noraristeromycin and their antiviral properties.

An enantiospecific synthesis of 3-deaza-5'-noraristeromycin as its dihydrochloride ((-)-6) has been accomplished in six steps beginning with the reaction of (+)-(1R,4S)-4-hydroxy-2-cyclopenten-1-yl acetate with 4-chloro-1H-imidazo[4,5-c]pyridine. The preparation of 7-deaza-5'-noraristeromycin ((-)-7) was described previously. Compounds (-)-6 and (-)-7 were evaluated for antiviral activity against a large number of viruses. Compound (-)-6 produced an antiviral activity pattern similar to 5'-noraristeromycin but was less potent. Compound (-)-6 inhibited CEM cell proliferation at a 50% inhibitory concentration of 27 micrograms/mL but proved not inhibitory to HEL cell proliferation and not toxic to E6SM, HeLa, Vero, and MDCK cells at concentrations up to 200 micrograms/mL. While (-)-6 showed inhibition of S-adenosyl-L-homocysteine (AdoHcy) hydrolase, it was less inhibitory than 5'-noraristeromycin. Compound (-)-7 displayed no antiviral properties or inhibitory effects toward AdoHcy hydrolase.

Adenosine↗