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Biomedical subjects

R Snoeck

Publications and source records attributed to R Snoeck.

At least 109 records · Page 6Linked to original sources
PubMed1995

Synthesis, biological evaluation, and structure analysis of a series of new 1,5-anhydrohexitol nucleosides.

In view of the selective anti-HSV activity of 1,5-anhydro-2,3-dideoxy-2- (5-iodouracil-1-yl)-D-arabino-hexitol, a series of novel 1,5-anhydrohexitol nucleosides were synthesized and evaluated for their inhibitory activity against several viruses. The 5-iodouracil 3 and the 5-ethyluracil 4 derivatives are highly selective TK-dependent inhibitors of HSV-1 and HSV-2. Broad anti-herpes virus activity was noticed for 5-fluorocytosine 6 and 2,6-diaminopurine 10 analogues. From a transport study of 3, using the thymidine influx competition method, one can conclude that intracellular uptake of this compound most probably occurs by passive diffusion. X-ray analysis of compounds 3 and 9 showed that the heterocyclic base of 1,5-anhydrohexitol pyrimidine and purine is placed in the axial position and that the sugar ring adopts a slightly distorted chair conformation.

Animals↗
PubMed1995

Successful treatment of a squamous papilloma of the hypopharynx-esophagus by local injections of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine.

Human papillomaviruses (HPV) are associated with benign lesions and show specificity towards the location or tissues that they infect. HPVs are responsible for warts. Among more than 60 different HPV types known to occur in humans, a strong association has been found between types 16 and 18 and cervical cancer, and such an association is also suspected for types 31, 33, 35, 45, 51, 52, and 56. We describe the effects of (S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl)cytosine (HPMPC), following local intratumoral injection, in a 69-year-old woman with hypopharyngeal and esophageal papillomatous lesions, polymerase chain reaction (PCR) positive for HPV types 16 and 18, that relapsed after surgery and that also failed to respond to Nd-Yag laser photocoagulation and alpha-interferon treatment (6 x 10(6) U five times a week for 4 weeks followed by three times a week for 2 months). HPMPC was given at 1.25 mg/kg, with a sclerosing needle, through the biopsy channel of a video-endoscope, directly into the tumor, from March until July 1993 at seven different occasions. The first four injections were given at an interval of 1 week at the level of the hypopharynx. The next three injections were given at an interval of 3 to 5 weeks. During the fourth to the seventh session, half of the dose was injected into the hypopharyngeal and the other half into the esophageal tumor. Three further injections of HPMPC were administered at the level of the esophageal tumor in September 1993 with 2-week intervals. After HPMPC treatment, the lesions became smaller and flat until they completely disappeared.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1995

Comparative activity of selected antiviral compounds against clinical isolates of varicella-zoster virus.

Sixteen freshly isolated varicella-zoster virus (VZV) strains were evaluated in vitro, in parallel with two reference strains expressing a functional thymidine kinase (TK+) (Oka and YS) and two thymidine kinase-deficient mutants (TK-) (07-1 and YS-R), for their susceptibility to a broad range of antiviral compounds. The following compounds were included: acyclovir (ACV), brivudine (BVDU), sorivudine (BVaraU), other BVDU congeners such as BTDU, CTDU, CVDC and CVDU, ganciclovir (GCV), FIAC, araT, araA, araC, foscarnet (PFA), phosphonoacetic acid (PAA), the acyclic nucleoside phosphonates HPMPC, cHPMPC, HPMPA, cHPMPA, HPMPc3A, PMEA and PMEDAP, the N7-isomeric acyclic nucleoside analogue N7AP, penciclovir (PCV), compounds 882C87 and H2G and two oxetanocin derivatives OXT-A and OXT-G. Fourteen of the 16 clinical isolates displayed the following order of decreasing selectivity against VZV: BVaraU > BVDU > CVDU approximately CVDC > H2G > N7AP approximately CTDU approximately BTDU approximately OXT-G approximately 882C87 > ACV > FIAC approximately araT > HPMPC approximately cHPMPC approximately HPMPA approximately HPMPc3A approximately cHPMPA > PCV approximately GCV approximately OXT-A > PMEDAP approximately PMEA > PFA approximately PAA approximately araA > araC. Two VZV strains (isolated from the cerebrospinal fluid of an AIDS patient) that were shown to have a truncated TK were clearly resistant to all the compounds that need the viral TK for their phosphorylation, while sensitivity to the acyclic nucleoside phosphonates, PFA, PAA, OXT-A and araA, remained unchanged. A slight (5- and 10-fold) increase was noted in the 50% inhibitory concentration of N7AP and OXT-G, respectively, for the TK- VZV strains as compared to the TK+ VZV strains. Ganciclovir and FIAC also showed a marked decrease in their activity against these two strains, but this was not as pronounced as for the other viral TK-dependent drugs. From our results, it appears that although acyclic nucleoside phosphonates may not have as favourable a therapeutic index as drugs requiring the viral TK, they should be considered for the treatment of TK- VZV life-threatening infections that are resistant to the viral TK-dependent drugs.

Antiviral Agents↗
PubMed1995

In vivo antiherpesvirus activity of N-7-substituted acyclic nucleoside analog 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine.

The efficacy of 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine (S2242) was evaluated in several animal models for herpesvirus infections. Compound S2242 was more effective than acyclovir (i) when administered subcutaneously in a model for herpes simplex virus type 1 (HSV-1)-induced mortality in immunocompetent mice and (ii) when applied topically to hairless (hr/hr) mice that had been infected intracutaneously with HSV-2. In SCID (severe combined immune deficient) mice that had been infected with a thymidine kinase-deficient HSV-1 strain, S2242 (administered subcutaneously at a dosage of 50 mg/kg/day) completely protected against virus-induced mortality whereas foscarnet was less effective and acyclovir had no or little protective effect. Compound S2242 was far more effective than ganciclovir in preventing or delaying murine cytomegalovirus-induced mortality in immunocompetent and SCID mice. The compound was more effective when a given dose was fractionated and administered on subsequent days than when this dose was administered in one single injection. A 5-day treatment course with S2242 (10 and 50 mg/kg/day) for newborn mice that had been infected with a lethal dose of murine cytomegalovirus suppressed virus-induced mortality. Compound S2242 had no inhibitory effect on the growth of weanling (at 50 mg/kg for 5 days) and 3- to 4-week-old mice (at doses of 50 to 200 mg/kg for 6 weeks). However, akin to ganciclovir, compound S2242 significantly reduced testicle weight, testicle morphology, and spermatogenesis.

Acyclovir↗
PubMed1995

Susceptibilities of several drug-resistant herpes simplex virus type 1 strains to alternative antiviral compounds.

Resistant herpes simplex virus type 1 strains were obtained under the selective pressure of acyclovir, ganciclovir, bromovinyldeoxyuridine, foscarnet, 2-phosphonylmethoxyehtyl (PME) derivatives of adenine and 2,6-diaminopurine, 3-hydroxy-2-phosphonylmethoxypropyl derivatives of adenine and cytosine, and 2-amino-7-(1,3-dihydroxy-2-propoxymethyl)purine (S2242). The drug susceptibility profiles of resistant strains point to differences in the modes of action of PME and 3-hydroxy-2-phosphonylmethoxypropyl derivatives and common mechanisms of action of foscarnet, S2242, and PME derivatives against herpes simplex virus type 1 replication.

Antiviral Agents↗
PubMed1994

Tricyclic analogues of acyclovir and ganciclovir. Influence of substituents in the heterocyclic moiety on the antiviral activity.

The effect of substitution in the tricyclic moiety of 3,9-dihydro-9-oxo-5H-imidazo[1,2-alpha]purine (1,N-2-ethenoguanine) analogues of acyclovir (1) and ganciclovir (2) on their physical properties and antiherpetic activity was investigated by synthesizing a series of compounds substituted in the 2, 6, or 7 position (6-14). Substitution in the 6-position with phenyl or 4-biphenylyl resulted in fluorescent compounds (7, 9, 13, 14). In general, the substituent in the 6 position potentiated the antiviral activity. The fluorescent 6-phenyl derivatives: 3,9-dihydro-3-[(2-hydroxyethoxy)methyl]-9-oxo-6-phenyl-5H-imidaxo[ 1,2-alpha]purine (7) and its 3-[(1,3-dihydroxy-2-propoxy)methyl] congener (13) were the most potent tricyclic analogues of 1 and 2, respectively. Compound 7 was inhibitory to TK+ HSV-1, TK+ HSV-2, and TK+ VZV within the concentration range of 0.2-2.0 micrograms/mL, well below the cytotoxicity threshold (50 to > 100 micrograms/mL). Compound 13 was inhibitory to TK+ HSV-1 and TK+ HSV-2 within the concentration range of 0.005-0.3 microgram/mL and to TK+ and TK- VZV within the concentration range of 0.4-3 micrograms/mL (cytotoxicity threshold > 200 micrograms/mL). Both 7 and 13 seem to be promising candidate compounds for the noninvasive diagnosis of herpesvirus infections.

Acyclovir↗
PubMed1994

Antiviral activity of a sulphated polysaccharide from the red seaweed Nothogenia fastigiata.

The antiviral activity of polysaccharide fractions obtained from water extracts of the red seaweed Nothogenia fastigiata was investigated. Fraction F6, corresponding to a sulphated xylomannan, was found to inhibit efficiently the replication of herpes simplex virus type 1 (HSV-1). Furthermore, F6 selectively inhibited the replication of several other enveloped viruses including herpes simplex virus type 2, human cytomegalovirus (HCMV), respiratory syncytial virus, influenza A and B virus, Junin and Tacaribe virus and simian immunodeficiency virus. F6 was only weakly active against human immunodeficiency virus type 1 and 2. The mode of action of F6 against HSV-1 and HCMV could be ascribed to an inhibitory effect on virus adsorption.

Antiviral Agents↗
PubMed1994

Synthesis and antiviral activities of 8-alkynyl-, 8-alkenyl-, and 8-alkyl-2'-deoxyadenosine analogues.

Palladium-catalyzed cross-coupling of 8-bromo-2'-deoxyadenosine with terminal alkynes in the presence of copper(I) iodide in dimethylformamide resulted in a series of 8-(1-alkyn-1-yl)-2'-deoxyadenosines. Hydrogenation of alkynyl derivatives over 10% Pd/C under atmospheric pressure gave 8-n-alkyl analogues in nearly quantitative yields. On partial saturation of heptynyl, pentynyl, and propynyl derivatives over Lindlar catalyst, the corresponding cis-olefins were obtained along with minor amounts of trans isomers. Of the analogues tested, the following showed some activity, i.e. they were found to be active at concentrations that were at least 3-fold lower than the cytotoxic concentrations: the 8-heptynyl derivative against vaccinia virus (VV), vesicular stomatitis virus (VSV), cytomegalovirus (CMV), and respiratory syncytial virus (RSV); the 8-propyl derivative against varicella-zoster virus (VZV) and CMV; the 8-pentyl derivative against CMV; the 8-heptyl derivative against VV, CMV, RSV, and influenza A; and the 8-heptenyl derivative against VV, RSV, and influenza A. The unsubstituted 2'-deoxyadenosine did not show any antiviral effect, except against RSV. Except for 8-propyl-dA, the antivirally active dA analogues were rather inhibitory to the growth of human embryonic lung cells. The most cytotoxic was the 8-ethynyl derivative.

Adenosylhomocysteinase↗
PubMed1994

An epimer of 5'-noraristeromycin and its antiviral properties.

A derivative of 5'-noraristeromycin epimeric at the 5'-nor center ((-)-3) has been prepared enantiospecifically in three steps from (+)-((1R,4S)-4-hydroxy-2-cyclopenten- 1-yl acetate. Compound (-)-3 was evaluated for antiviral activity against a large number of viruses and found to display marked activity against varicella-zoster virus, vaccinia virus, vesicular stomatitis virus, parainfluenza virus, reovirus, and cytomegalovirus. A similar antiviral activity spectrum was shown by the S-adenosylhomocysteine hydrolase inhibitors neplanocin A and carbocyclic 3-deazaadenosine. While equally potent as neplanocin A against most of the viruses tested, compound (-)-3 was significantly less cytotoxic. The results of this study suggest that (-)-3 should be pursued for the treatment of those virus infections [that is, pox (VV), rhabdo (VSV), paramyxo (parainfluenza), and reo] that appear to be exquisitively sensitive to the compound.

Adenosine↗
PubMed1994

Antiviral enantiomeric preference for 5'-noraristeromycin.

In order to determine if the potent antiviral properties of (+/-)-5'-noraristeromycin reside in one of its enantiomers, an analysis of each enantiomer has been carried out. A five-step route to the (+)-stereoisomer is described from (+)-(1R,4S)-4-hydroxy-2-cyclopenten-1-yl acetate, whereas the synthesis of the (-)-enantiomer had been reported previously from the same starting material. The (-)-2 and (+)-2 enantiomers were evaluated for antiviral activity against a large number of viruses and found to display an antiviral activity spectrum characteristic of (S)-adenosyl-L-homocysteine hydrolase inhibitors. The (-)-enantiomer retained the significant anticytomegalovirus properties previously reported for the racemic 2 and was, on the average, 10-fold more potent than (+)-2 in inhibiting virus replication, tumor cell growth, and (S)-adenosyl-L-homocysteine hydrolase activity.

Adenosine↗
PubMed1994

Meningoradiculoneuritis due to acyclovir-resistant varicella zoster virus in an acquired immune deficiency syndrome patient.

Varicella zoster virus (VZV) is recognized as one of the major viral pathogens reactivated in patients with the acquired immune deficiency syndrome (AIDS). We report the case of meningoradiculoneuritis in an AIDS patient,associated with the isolation in the cerebrospinal fluid (CSF) of a thymidine kinase (TK)-deficient, acyclovir (ACV)-resistant strain of VZV. Although the virus was sensitive in vitro to phosphonoformate (PFA), the patient did not improve during PFA therapy and finally died. Several VZV strains isolated from this patient (including two isolates from the patient's CSF) were analyzed for their TK activity and subsequently the viral TK gene was sequenced showing a major deletion leading to a truncated protein. Their susceptibility to several antiviral agents including ACV, PFA, (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU), 9-beta-D-arabinofuranosyladenine (vidarabine), (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl) cytosine (HPMPC), and (S)-9-(3-hydroxy-2-phosphonyl-methoxypropyl)adenine (HPMPA) was evaluated. All the virus strains isolated from this patient remained sensitive to HPMPA and HPMPC, pointing to the potential usefulness of these acyclic nucleoside phosphonates for the treatment of ACV-resistant VZV infections in immunocompromised patients.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Successful treatment of progressive mucocutaneous infection due to acyclovir- and foscarnet-resistant herpes simplex virus with (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC).

The acyclic nucleoside phosphonate (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC) was used topically for the treatment of persistent mucocutaneous infections in two cases. One patient with AIDS suffered from a perineal lesion due to infection with herpes simplex virus type 2 (HSV-2) and did not respond to acyclovir and was intolerant of foscarnet. A bone marrow transplant recipient developed orofacial lesions due to infection with herpes simplex virus type 1 (HSV-1) that failed to respond to therapy with both acyclovir and foscarnet. After topical application of HPMPC, the HSV-2 lesions completely resolved. However, the lesions recurred 3 weeks later, and, upon subsequent treatment with HPMPC, regressed. On recurrence, the virus was found to be sensitive to acyclovir, which the patient was given. Again HSV-2, which was resistant to acyclovir, emerged; similar observations were made after another cycle of HPMPC therapy. The HSV-1 isolates were resistant to acyclovir and foscarnet. Following local HPMPC treatment, the lesions regressed, but after 1 week, a second course of topical HPMPC therapy had to be instituted for recurrent infection. The lesions again regressed, and as the recurrent virus was sensitive to acyclovir, the patient was successfully treated with the drug. The results of this study point to the potential usefulness of topical HPMPC in the treatment of immunocompromised patients with HSV-related mucocutaneous infections that are refractory to therapy with acyclovir and/or foscarnet.

AIDS-Related Opportunistic Infections↗
PubMed1994

The N-7-substituted acyclic nucleoside analog 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine is a potent and selective inhibitor of herpesvirus replication.

2-Amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine (compound S2242) represents the first antivirally active nucleoside analog with the side chain attached to the N-7 position of the purine ring. Compound S2242 strongly inhibits the in vitro replication of both herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) (50% effective concentration [EC50], 0.1 to 0.2 microgram/ml), varicella-zoster virus (EC50, 0.01 to 0.02 microgram/ml) and thymidine kinase (TK)-deficient strains of HSV (EC50, 0.4 microgram/ml) and varicella-zoster virus (EC50, 0.2 to 0.5 microgram/ml). Potent activity was also observed against murine cytomegalovirus (EC50, 1 microgram/ml), human cytomegalovirus (HCMV) (EC50, 0.04 to 0.1 microgram/ml), and human herpesvirus 6 (EC50, 0.0005 microgram/ml). Compound S2242 (i) was not cytotoxic to confluent Vero, HeLa, or human fibroblast cells at concentrations of > 100 micrograms/ml, (ii) proved somewhat more cytostatic to Vero, HEL, HeLa, and C127I cells than ganciclovir, and (iii) was markedly more cytostatic than ganciclovir to the growth of the human lymphocytic cell lines HSB-2 and CEM degrees. In contrast to ganciclovir, (i) compound S2242 proved not to be cytocidal to murine mammary carcinoma (FM3A) cells transfected with the HSV-1 or HSV-2 TK gene, (ii) exogenously added thymidine had only a limited effect on its anti-HSV-1 activity, and (iii) the compound was not phosphorylated by HSV-1-encoded TK derived from HSV-1 TK-transfected FM3A cells, indicating that the compound is not activated by a virally encoded TK. Compound S2242 inhibited (i) the expression of late HCHV antigens at an EC50 of 0.07 microgram/ml (0.6 microgram/ml for ganciclovir) and (ii) HCMV DNA synthesis at an EC50 of 0.1 microgram/ml (0.32 microgram/ml for ganciclovir), i.e., values that are close to the EC50S for inhibition of HCMV-induced cytopathogenicity. Neither ganciclovir nor S2242 had any effect on the expression of immediate-early HCMV antigens, which occurs before viral DNA synthesis. In time-of-addition experiments, S2242 behaved like ganciclovir and acyclovir; i.e., the addition of the drugs could be delayed until the onset of viral DNA synthesis.

Animals↗
PubMed1994

Synthesis and antiviral activity of three pyrazole analogues of distamycin A.

The synthesis of three new monopyrazole analogues of the antiviral compound distamycin A is reported. Suitably protected 4-amino-1-methylpyrrole-2-carboxylic acid and 3-amino-1-methylpyrazole-5-carboxylic acid derivatives were chosen as starting materials. The construction of the trimeric polyamide framework was accomplished by assembly of the monomeric precursors under condensing conditions by analogy with our previous methodology, although with significant improvements in some pivotal steps. After chromatographic purification and spectroscopic characterisation, the analogues were assayed for antiviral activity. Compounds 7a-c inhibited vaccinia virus at a concentration similar to or lower than distamycin A and the related antibiotic netropsin. Analogues 7b and 7c exhibited an antiviral effect comparable to those of distamycin A and netropsin against HSV-1 and HSV-2, whereas their antiviral activity against several other viruses including HIV-1 and HIV-2 was somewhat lower. The cellular toxicity of 7a-c toward different host cell types proved to be of similar magnitude or lower than those of distamycin A and netropsin.

Animals↗
PubMed1994

Decreased production of cytokines after cytomegalovirus infection of marrow-derived stromal cells.

Cytomegalovirus (CMV) infection is frequently associated with graft failure in bone marrow transplant patients; the pathogenesis of this myelosuppression in not clearly understood. We have previously documented that CMV-induced myelosuppression is related to an alteration of the marrow microenvironment. To further investigate the effect of CMV on stromal cell function, conditioned media (CM) from CMV-infected or uninfected stromal cells were tested for their capacity to promote the growth of granulocyte/macrophage colony-forming cells (CFU-GM) and for their concentration in colony-stimulating factors (CSFs) such as interleukin-3 (IL-3), IL-6, granulocyte-macrophage and granulocyte colony-stimulating factors (GM-CSF and G-CSF). CM from CMV-infected stromal cells failed to sustain granulocyte-macrophage colony-forming unit (CFU-GM) growth. The production of IL-6, GM-CSF, and G-CSF, measured by enzyme-linked immunosorbent assay (ELISA), was 21,150 +/- 3392, 57 +/- 15, and 2340 +/- 717 pg/mL, respectively, in CMV-infected stromal cells stimulated by lipopolysaccharide (LPS) and was significantly decreased (p < 0.01) from the control values (177,138 +/- 98,692, 113 +/- 20, and 5533 +/- 1306 pg/mL). These results suggest that the myelosuppressive effect of CMV is primarily due to a lack of CSF production. To further document this hypothesis, primitive marrow progenitor cells (blast colony-forming cells [Bl-CFC]) cultured on CMV-infected stromal layer have been grown in the presence of IL-3 (20 ng/mL), IL-6 (20 ng/mL), GM-CSF (40 ng/mL), and G-CSF (50 ng/mL). Used alone, all these CSFs partially reverse the CMV-induced inhibition of Bl-CFC growth; the combination of these CSFs completely restores normal Bl-CFC values. These data strongly suggest that CMV-induced myelosuppression is related to the lack of CSF production by the cells of the marrow microenvironment.

Adolescent↗
PubMed1993

Synthesis and antiviral activity of 5'-deoxypyrazofurin.

In searching for derivatives of pyrazofurin that could display antiviral properties by means that do not require C-5' phosphorylation, 5'-deoxypyrazofurin (3) has been synthesized in six steps from methyl5-deoxy-2,3-O-isopropylidene-beta-D-ribofuranoside (4). Compound 3 was evaluated for antiviral activity against a large number of viruses including herpes-, pox-, myxo-, toga-, arena-, rhabdo-, picorna-,reo-, and retroviruses. Compound 3 proved active against respiratory syncytial virus (in HeLa cells), vaccinia virus (in embryonic skin-muscle fibroblast cells), vesicular stomatitis virus (in HeLa cells), and influenza A virus (in Madin-Darby canine kidney cells) at concentrations (ranging from 4 to 20 micrograms/mL) that were nontoxic to the confluent host cell cultures.

Animals↗