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Biomedical subjects

J Balzarini

Publications and source records attributed to J Balzarini.

At least 343 records · Page 19Linked to original sources
PubMed1992

Nucleic acid related compounds. 74. Synthesis and biological activity of 2'(and 3')-deoxy-2'(and 3')-methylenenucleoside analogues that function as mechanism-based inhibitors of S-adenosyl-L-homocysteine hydrolase and/or ribonucleotide reductase.

Treatment of 2-amino-6-chloro-9-(beta-D-ribofuranosyl)purine (21) with TBDMS chloride/imidazole/DMF gave a separable mixture of 5'-O, 2',5'-bis-O (22), 3',5'-bis-O (23), and 2',3',5'-tris-O-TBDMS derivatives. Oxidation of 22 and 23 with CrO3/pyridine/Ac2O, treatment of the respective ketonucleosides with methylenetriphenylphosphorane, and deprotection gave 2-amino-6-chloro-9-[3(and 2)-deoxy-3(and 2)-methylene- beta-D-erythro-pentofuranosyl]purines (28 and 37) that were converted into other 2-amino-6-substituted-purine analogues. Tubercidin was converted into 2'-deoxy-2'-methylenetubercidin (49) by an analogous route. Inactivation of S-adenosyl-L-homocysteine hydrolase by 2'- and 3'-methyleneadenosine analogues was investigated. Mechanism-based inhibition of S-adenosyl-L-homocysteine hydrolase and anticancer and antiviral activities of 2'(and 3')-deoxy-2'(and 3')-methylenenucleoside analogues are discussed.

Adenosylhomocysteinase↗
PubMed1992

Geiparvarin analogues. 3. Synthesis and cytostatic activity of 3(2H)-furanone and 4,5-dihydro-3(2H)-furanone congeners of geiparvarin, containing a geraniol-like fragment in the side chain.

Continuing our study on the structural features of geiparvarin (1), responsible for cytostatic activity, a series of 4,5-dihydro-3(2H)-furanones 10a-f and of 3(2H)-furanones 11a-f as well as 2",3"-dihydrogeiparvarin (14) have been designed and synthesized. Their cytostatic activity was evaluated against proliferation of murine (L1210, FM3A) and human (Raji, Molt/4F, and MT4) tumor cells. Modifications in the region of the olefinic double bond by introduction of the characteristic alkenyl side chain of ascofuranone (compounds 10a-f and 11a-f) markedly decreased the cytostatic activity as compared to geiparvarin itself, but this effect does not seem to be correlated to the presence of the furanone moiety linked to the alkenyl chain or to the ability to afford Michael type adducts. Replacement of the coumarin portion by other aromatic rings did not alter the cytostatic activity. The essential inactivity of 2",3"-dihydrogeiparvarin (14) points to the importance of the 3(2H)-furanone ring system in the cytostatic activity; consequently, this moiety may be considered as the determinant pharmacophore for antitumor activity, while the side chain plays a rather modulatory role.

Acyclic Monoterpenes↗
PubMed1992

2',5'-Bis-O-(tert-butyldimethylsilyl)-3'-spiro-5''-(4''-amino-1'',2''- oxathiole-2'',2'-dioxide)pyrimidine (TSAO) nucleoside analogues: highlyselective inhibitors of human immunodeficiency virus type 1 that are targeted at the viral reverse transcriptase.

A series of pyrimidine nucleoside analogues containing [2',5'-bis-O-(tert-butyldimethylsilyl)-3'-spiro-5''-(4''-amino- 1'',2''-oxathiole-2'',2''-dioxide)]-beta-D-ribofuranose as the pentose were found to inhibit human immunodeficiency virus type 1 [HIV-1(IIIB)] replication at a concentration of 0.06-0.8 microM but were not cytotoxic at a 1000- to 10,000-fold higher concentration. These nucleoside derivatives were also effective against various other HIV-1 strains, including those resistant to 3'-azido-3'-deoxythymidine, but not against HIV-2, simian immunodeficiency virus, Moloney murine sarcoma virus, or other RNA or DNA viruses. They proved to be highly specific inhibitors of the RNA-dependent DNA polymerase function of the HIV-1 reverse transcriptase, showing no marked inhibition of the HIV-1 reverse transcriptase-associated DNA-dependent DNA polymerase activity, HIV-2 reverse transcriptase, DNA polymerase alpha, herpes simplex virus 1 DNA polymerase, or Thermus aquaticus DNA polymerase.

Antiviral Agents↗
PubMed1992

New neplanocin analogues. 1. Synthesis of 6'-modified neplanocin A derivatives as broad-spectrum antiviral agents.

Novel neplanocin A analogues modified at the 6'-position, i.e., 6'-deoxy analogues (2, 3, 6, 9, 20), 6'-O-methylneplanocin A (15), and 6'-C-methylneplanocin A's (22a and 22b) have been synthesized and evaluated for their antiviral activity in a wide variety of DNA and RNA virus systems. These compounds showed an activity spectrum that conforms to that of S-adenosylhomocysteine hydrolase inhibitors. They were particularly active against pox- (vaccinia), paramyxo-(parainfluenza, measles, respiratory syncytial), arena- (Junin, Tacaribe), rhabdo- (vesicular stomatitis), reo-, and cytomegalovirus. In order of (increasing) antiviral activity, the compounds ranked as follows: 3 less than 15 approximately 20 less than 6 less than 9 approximately 2 less than 22a. Of the two diastereomeric forms of 22, only 22a was active; 22a surpassed neplanocin A both in antiviral potency and selectivity. Compound 22a appears to be a promising candidate drug for the treatment of pox-, paramyxo-, arena-, rhabdo-, reo-, and cytomegalovirus infections.

Adenosine↗
PubMed1992

Efficacy of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine and 9-(1,3-dihydroxy-2-propoxymethyl)guanine for the treatment of murine cytomegalovirus infection in severe combined immunodeficiency mice.

Mice with severe combined immunodeficiency (SCID) inoculated intraperitoneally with murine cytomegalovirus (MCMV) develop a wasting syndrome at 3-4 days and die at 6-9 days after the infection. 9-(1,3-Dihydroxy-2-propoxymethyl)guanine (DHPG, ganciclovir) and (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC) were compared for their efficacy against MCMV-induced disease and mortality in SCID mice. Under all treatment conditions, i.e., administration of the test compounds for 5 consecutive days starting on the day of infection (day 0), for 5 consecutive days starting on day 4 after the infection, 2 periods of 3 consecutive days starting on day 0 and day 9 after infection, or as a single dose on day 3 before infection, HPMPC proved far superior to ganciclovir in delaying the onset of the disease and increasing the lifespan of the MCMV-infected mice.

Animals↗
PubMed1992

Activity of different antiviral drug combinations against human cytomegalovirus replication in vitro.

The effects of different antiviral drug combinations on the replication of various human cytomegalovirus (CMV) strains in human embryonic lung (HEL) fibroblasts were evaluated. HPMPC combined with either ganciclovir, foscarnet or acyclovir showed additive to synergistic inhibition of CMV replication. Combinations of zidovudine with HPMPC, ganciclovir, foscarnet or acyclovir also resulted in additive to synergistic inhibition of CMV replication. Synergism tended to be higher for the clinical CMV isolates than for the reference strains AD-169 and Davis. Suppression of CMV replication was obtained at lower drug concentrations when the drugs were combined than when the drugs were used alone. At the highest drug concentrations used in the antiviral activity experiments, neither drug alone nor its combination suppressed host cell growth. If higher drug concentrations were used, zidovudine increased the inhibitory effects of ganciclovir, acyclovir and foscarnet but not of HPMPC, on cell proliferation. Use of combinations in the therapy of CMV infections may be considered to enhance drug efficacy, to reduce toxicity and, possibly, to diminish the risk of emergence of drug-resistant virus strains.

Antiviral Agents↗
PubMed1992

Sulfated polymers inhibit the interaction of human cytomegalovirus with cell surface heparan sulfate.

Several sulfated polysaccharides (dextran sulfate, pentosan polysulfate, heparin) and copolymers of acrylic acid with vinylalcohol sulfate have proved to be potent inhibitors of human cytomegalovirus (CMV) infectivity in vitro. Sulfated alpha-cyclodextrins are only weak inhibitors of CMV. A close correlation was found between the 50% inhibitory concentrations of the sulfated polymers for CMV cytopathogenicity, virus-cell binding, and expression of immediate early antigens (IEA) in human embryonic lung (HEL) cells. CMV particles bound specifically to heparin-Sepharose. Sulfated polymers specifically eluted the virus particles from this matrix. Enzymatic digestion of cell surface heparan sulfate, but not of chondroitin sulfate, prevented the cells from being infected with CMV. Moreover, radiolabeled CMV bound efficiently to, and were infective for wild-type Chinese hamster ovary (CHO) cells, whereas virus binding to, and infection of, mutant CHO cell lines that were deficient in either all glycosaminoglycans or heparan sulfate only was significantly impaired. The mechanism of action of the sulfated polymers can be attributed to an inhibitory effect on the binding of CMV particles to the host cells. Presumably, the sulfated polymers interact with the viral envelope site(s) involved in the attachment of the CMV virions to cell surface heparan sulfate.

Acrylic Resins↗
PubMed1992

Different pattern of activity of inhibitors of the human immunodeficiency virus in lymphocytes and monocyte/macrophages.

Monocyte/macrophages (M/M) are important targets for HIV in the body, and represent the majority of cells infected by the virus in some body compartments such as the central nervous system (CNS). M/M can be different from T-lymphocytes in terms of surface antigens, cell replication and drug metabolism. Thus, we evaluated, in M/M and in T-lymphocytes, the pattern of viral inhibition induced by various anti-HIV drugs, and assessed some of the mechanisms of action related to such antiviral activity. Inhibitors of HIV binding on CD4 receptors have similar activity in M/M and T-lymphocytes, while AZT and other dideoxynucleosides (ddN) are in general more active against HIV in M/M than in T-lymphocytes. This phenomenon can be related to the increased ratio in M/M of ddN-triphosphate/deoxynucleoside-triphosphate, and can at least in part explain the ability of zidovudine and didanosine in improving neurological dysfunctions in AIDS patients. Moreover, the antiviral activity of AZT (but not of other ddN- or HIV-binding inhibitors) is potently enhanced by cytokines like granulocyte-macrophage colony stimulating factor (GM-CSF) in M/M, while anti-HIV activity of TIBO compounds in M/M is not down-modulated by GM-CSF and other cytokines. Finally, non-toxic concentrations of adriamycin, an anticancer drug reported to be active against DNA viruses, can inhibit HIV replication in M/M (but not in T-lymphocytes). Taken together, these results suggest that M/M are selective targets for HIV with peculiarities different from those of T-lymphocytes. Thus, promising anti-HIV compounds should be evaluated both in T-cells and in M/M before reaching clinical trials. This may help in selecting drugs with good chances of being effective in patients with HIV-related disease.

Adenine↗
PubMed1992

The mannose-specific plant lectins from Cymbidium hybrid and Epipactis helleborine and the (N-acetylglucosamine)n-specific plant lectin from Urtica dioica are potent and selective inhibitors of human immunodeficiency virus and cytomegalovirus replication in vitro.

A series of four mannose(Man)-, three N-acetylglucosamine (GlcNAc)n-, ten N-acetylgalactosamine/galactose(GalNAc/Gal)-, one 5-acetylneuraminic acid (alpha-2,3-Gal/GalNAc)- and one 5-acetylneuroaminic acid(alpha-2,6-Gal/Gal-NAc)-specific plant agglutinins were evaluated for their antiviral activity in vitro. the mannose-specific lectins from the orchid species Cymbidium hybrid (CA), Epipactis helleborine (EHA) and Listera ovata (LOA) were highly inhibitory to human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) in MT-4, and showed a marked anti-human cytomegalovirus (CMV), respiratory syncytial virus (RSV) and influenza A virus activity in HEL, HeLa and MDCK cells, respectively. The 50% effective concentration (EC50) of CA and EHA for HIV ranged from 0.04 to 0.08 micrograms/ml, that is about 3 orders of magnitude below their toxicity threshold (50% inhibitory concentration for MT-4 cell growth: 54 to 60 micrograms/ml). Also, the (GlcNAc)n-specific lectin from Urtica dioica (UDA) was inhibitory to HIV-1-, HIV-2-, CMV-, RSV- and influenza A virus-induced cytopathicity at an EC50 ranging from 0.3 to 9 micrograms/ml. The GalNAc/Gal-, alpha-2,3-Gal/GalNAc- or alpha-2,6-Gal/GalNAc-specific lectins were not inhibitory to HIV or CMV at non-toxic concentrations. CA, EHA and UDA proved to be potent inhibitors of syncytium formation between persistently HIV-1- and HIV-2-infected HUT-78 cells and CD4+ Molt/4 (clone 8) cells (EC50: 0.2-2 micrograms/ml). Unlike dextran sulfate, the plant lectins CA, EHA and UDA did not interfere with HIV-1 adsorption to MT-4 cells and RSV- and influenza A virus adsorption to HeLa and MDCK cells, respectively. They presumably interact at the level of virion fusion with the target cell.

Acetylglucosamine↗
PubMed1992

Selective inhibition of HIV replication by adriamycin in macrophages but not in lymphocytes.

Adriamycin (ADR) is an anticancer drug commonly used in the treatment of HIV-related cancers. Due to its effect on DNA metabolism, ADR might be able to modulate HIV replication in monocyte-macrophages (M/M), resting cells potentially less sensitive to the toxic effect of this drug. Thus, we assessed the efficacy of ADR against HIV replication in both lymphocytes and M/M. We further investigated the mechanism(s) of action of ADR and its potential synergistic activity with zidovudine (AZT) or alpha-interferon (IFN alpha). ADR consistently inhibited viral replication in M/M: 50% viral inhibition was obtained with 0.005 micrograms/ml ADR, while greater 90% viral inhibition was obtained with 0.05 micrograms/ml ADR. No cell toxicity was seen in M/M at concentrations up to 0.5 micrograms/ml. No anti-HIV activity was shown by ADR in lymphocytes at concentrations up to 0.05 micrograms/ml, that is also the toxic dose 50% (TCID50 for these cells). ADR neither inactivates HIV virions nor affects HIV binding with CD4 receptors. No inhibition of HIV reverse transcriptase by ADR was found at concentrations at least 2,000-fold greater than the 50% HIV inhibitory concentration in M/M. Molecular analysis by polymerase chain reaction (PCR) suggests that ADR substantially affects virus DNA production at concentrations that inhibit viral replication. Finally, late stages of HIV replication were not affected by ADR. At least additive effects of the association ADR + AZT and ADR + IFN alpha were obtained against de novo HIV infection of M/M.(ABSTRACT TRUNCATED AT 250 WORDS)

Antiviral Agents↗
PubMed1992

[2',5'-Bis-O-(tert-butyldimethylsilyl)]-3'-spiro-5''-(4''-amino-1'',2''-oxathiole-2'',2''-dioxide) (TSAO) derivatives of purine and pyrimidinenucleosides as potent and selective inhibitors of human immunodeficiency virus type 1.

The [2',5'-bis-O-(tert-butyldimethylsilyl)]-3'-spiro-5''-(4''-amino- 1'',2''-oxathiole-2'',2''-dioxide) (TSAO) derivatives of ribofuranosylthymine, uridine, 5-bromouridine, 5-methylcytidine, inosine, and adenosine are potent and selective inhibitors of human immunodeficiency virus type 1 (HIV-1) but not of other retroviruses (HIV-2, simian immunodeficiency virus, or Moloney murine sarcoma virus). The 50% effective concentration (EC50) of the most active TSAO congeners for inhibition of HIV-1 replication ranged from 0.034 to 0.44 microgram/ml. The 50% cytotoxic concentration (CC50) affecting the viability of MT-4 cells ranged from 2.35 to 18 micrograms/ml. The TSAO thymine derivative proved to be a highly selective inhibitor of HIV-1 reverse transcriptase but not of HIV-2 reverse transcriptase and DNA polymerase alpha. Introduction of an alkyl or alkenyl function at N3 of the thymine ring markedly decreased cytotoxicity but did not affect the antiviral activity of the compounds. The most potent (EC50, 0.034 microgram/ml) and most selective (CC50/EC50, 4088) inhibitor of HIV-1 replication proved to be the N3-methyl derivative of (1-[2',5'-bis-O-(tert-butyldimethylsilyl)beta-D-ribofuranosyl]thymine)- 3'-spiro-5''-(4''-amino-1'',2''-oxathiole-2'',2''-dioxide). This compound should be considered as a promising drug candidate for the treatment of HIV-1 infections.

Antiviral Agents↗
PubMed1992

Mechanism of anti-human immunodeficiency virus action of polyoxometalates, a class of broad-spectrum antiviral agents.

Various polyoxometalates proved inhibitory to the replication of a number of enveloped DNA and RNA viruses, i.e., herpesviruses (herpes simplex and cytomegalo), togaviruses (Sindbis), paramyxoviruses (respiratory syncytial), rhabdoviruses (vesicular stomatitis), arenaviruses (Junin and Tacaribe), and retroviruses [human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2), simian immunodeficiency virus, and murine sarcoma virus]. The most potent compounds, i.e., JM1590 [K13[Ce(SiW11O39)2]. 26H2O] and JM2766 [K6[BGa(H2O)W11O39]. 15H2O], inhibited HIV-1 and simian immunodeficiency virus at concentrations as low as 0.008-0.8 microM. The polyoxometalates also inhibited giant cell formation in co-cultures of HIV-infected HUT-78 cells and uninfected MOLT-4 cells. Studies designed to unravel the mechanism of action of these compounds revealed that they inhibit the reverse transcriptase activity associated with HIV. The polyoxometalates also proved inhibitory to the binding of HIV-1 virions to the cells. From "time of addition" experiments, whereby the polyoxometalates were added at different times after virus infection, their mechanism of anti-HIV action could be attributed to inhibition of virus-cell binding. There was a good correlation (r = 0.84) between the inhibitory effects of the compounds on HIV-1-induced cytopathicity and their inhibitory effects on syncytium formation and a close correlation (r = 0.902) between their inhibitory effects on syncytium formation and their interaction with gp120, whereas there was no correlation between their anti-HIV-1 activity and their inhibitory effects on HIV-1 reverse transcriptase. In flow cytometric studies, the compounds did not interfere with the binding of OKT4A/Leu-3a monoclonal antibody to the CD4 receptor of uninfected cells, but they inhibited binding of anti-gp120 monoclonal antibody to HIV-1-infected cells. Thus, the binding of the polyoxometalates to the viral envelope glycoprotein gp120 is responsible for their anti-HIV activity.

Antiviral Agents↗
PubMed1992

Acyclic adenine nucleoside phosphonates in plasma determined by high-performance liquid chromatography with fluorescence detection.

9-(2-Phosphonylmethoxyethyl)adenine (PMEA), (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine (HPMPA), and (R,S)-9-(3-fluoro-2-phosphonylmethoxypropyl)adenine (FPMPA) are selective antiviral agents with activity against a broad spectrum of DNA viruses and retroviruses. A highly sensitive method has been developed to determine concentrations of these compounds in human plasma. Plasma samples containing PMEA, HPMPA, or FPMPA were treated with chloroacetaldehyde to yield the corresponding highly fluorescent 1,N6-ethenoadenine derivatives. Chromatographic separation combined with excitation at 254 nm and fluorescence detection at 425 nm allowed quantification of PMEA, HPMPA, and FPMPA within a concentration range of 0.25-4000 mumol/L. This method proved useful in accurately determining low PMEA concentrations in sera from PMEA-treated monkeys and cats. The assay should be applicable to the quantification of PMEA, HPMPA, and FPMPA in plasma and urine of humans treated with any of these drugs.

Adenine↗
PubMed1991

Mechanism of the potentiating effect of ribavirin on the activity of 2',3'-dideoxyinosine against human immunodeficiency virus.

Ribavirin enhances the anti-human immunodeficiency virus activity of 2',3'-dideoxyinosine (ddIno) in MT-4, CEM and peripheral blood lymphocyte cells. Ribavirin causes an increase in the levels of IMP, the presumed phosphate donor for the conversion of ddIno to ddIMP by 5'-nucleotidase. Consequently, ribavirin stimulates the conversion of ddIno to its antivirally active metabolite ddATP. Ribavirin also causes a marked depletion of the guanine nucleotide pools. The increase in IMP pool levels may result from (i) a direct inhibitory effect of ribavirin 5'-monophosphate on IMP dehydrogenase (which converts IMP to XMP) and (ii) an indirect inhibition of adenylosuccinate synthetase by the decreased GTP and dGTP pools (since GTP is an obligatory cofactor in the conversion of IMP to succinyl AMP). GTP depletion plays a key role in the accumulation of IMP and the resultant higher rate of ddIno phosphorylation to ddIMP and eventually ddATP. Our findings are in agreement with the observations that guanosine and 2'-deoxyguanosine, but not 2'-deoxyadenosine, reverse (i) the stimulatory effect of ribavirin on the anti-human immunodeficiency virus activity of ddIno and (ii) the accumulation of endogenous IMP pools as well as accumulation of [3H]IMP from exogenous [3H]hypoxanthine in ribavirin-treated cells.

Biotransformation↗
PubMed1991

1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (ribavirin) and 5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide (EICAR) markedly potentiate the inhibitory effect of 2',3'-dideoxyinosine on human immunodeficiency virus in peripheral blood lymphocytes.

Ribavirin and EICAR are two antiviral agents that share a similar antiviral activity spectrum and are targeted at inosine 5'-monophosphate (IMP) dehydrogenase. Neither ribavirin nor EICAR inhibit the replication of human immunodeficiency virus (HIV) in peripheral blood lymphocyte cells (PBL) at subtoxic concentrations. However, both compounds markedly potentiate the anti-HIV activity of 2',3'-dideoxyinosine (DDI) in PBL cells without a marked increase of toxicity. Both the increased IMP levels and the decreased guanine nucleotide levels caused by ribavirin and EICAR may be responsible for their potentiating effect on the anti-HIV activity of DDI.

Antiviral Agents↗
PubMed1991

Activity of acyclic nucleoside phosphonate analogues against human immunodeficiency virus in monocyte/macrophages and peripheral blood lymphocytes.

A number of acyclic nucleoside phosphonate analogues, including 9-(2-phosphonylmethoxyethyl)adenine (PMEA) and its 2,6-diaminopurine derivative PMEDAP, (R,S)-9-(3-fluoro-2-phosphonylmethoxypropyl)adenine [(R,S)-FPMPA] and its 2,6-diaminopurine derivative (R,S)-FPMPDAP were evaluated for their inhibitory effects on HIV-1 replication in two natural human cell systems, i.e. peripheral blood lymphocytes (PBL) and freshly prepared monocyte/macrophages (M/M). All compounds were potent inhibitors of HIV-1 replication in PBL [50% effective concentration (EC50): 0.94-3.9 microM] and M/M (EC50: 0.022-0.95 microM). In particular, (R,S)-FPMPA and (R,S)-FPMPDAP showed a greater antiviral selectivity than PMEA and PMEDAP due to the virtual lack of toxicity of the former compounds in these cell systems. Also, the antiviral selectivity of the acyclic nucleoside phosphonate analogues was much higher in M/M than in the human T-cell lines MT-4, ATH8 and CEM.

Antiviral Agents↗