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J Balzarini

Publications and source records attributed to J Balzarini.

At least 73 records · Page 4Linked to original sources
PubMed2001

Thiosugars. VIII. Preparation of new 4'-thio-L-lyxo pyrimidine nucleoside analogues.

Reaction of 1-O-acetyl-2,3,5-tri-O-benzyl-4-thio-L-lyxofuranose with silylated pyrimidine bases and subsequent deprotection with boron tribromide led to 4'-thio-L-lyxo pyrimidine nucleosides. The 5-bromo-6-methyl derivative was prepared from methyl 2,3,5-tri-O-acetyl-4-thio-L-lyxofuranoside. Deacetylation was performed with sodium methoxide. The anomers were separated by HPLC and their configurations assigned by NMR spectroscopy and X-ray structural analyses. The biological activity of the nucleosides was tested.

Acetylation↗
PubMed2001

Synthesis and anti-HIV activity of thymidine analogues bearing a 4'-cyanovinyl group and some derivatives thereof.

Treatment of 3'-O-tert-butyldimethylsilyl-2',5'-dideoxy-5'-oxothymidine (4) with potassium or magnesium nitromethanide afforded in good yield the resolvable epimeric mixture of the expected blocked nitronucleosides 5 which upon dehydration led to the corresponding E-nitroenofuranosylthymidine 6. Nucleophilic attack of cyanide onto the nitrovinyl group led to a nucleoside analogue bearing a terminal 1-cyanovinyl group (7), a soft electrophilic group which, upon reaction with benzeneselenol, underwent a conjugate addition to the phenylselenonucleoside derivative 9. All these compounds, eventually de-O-silylated, were subject of in vitro biological testing, some exhibiting interesting cytotoxic or antiviral properties.

Animals↗
PubMed2001

Mutation of Gln125 to Asn selectively abolishes the thymidylate kinase activity of herpes simplex virus type 1 thymidine kinase.

The broad substrate specificity of herpes simplex virus type 1 (HSV-1) thymidine kinase (TK) has provided the basis for selective antiherpetic therapy and, more recently, suicide gene therapy for the treatment of cancer. We have now constructed an HSV-1 TK mutant enzyme, in which an asparagine (N) residue is substituted for glutamine (Q) at position 125, and have evaluated the effect of this amino acid change on enzymatic activity. In marked contrast with wild-type HSV-1 TK, which displays both thymidine kinase and thymidylate kinase activities, the HSV-1 TK(Q125N) mutant was unable to phosphorylate pyrimidine nucleoside monophosphates but retained significant phosphorylation activity for thymidine and a series of antiherpetic pyrimidine and purine nucleoside analogs. The abrogation of HSV-1 TK-associated thymidylate kinase activity resulted in a 100-fold accumulation of the monophosphate form of (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) in osteosarcoma cells transfected with the HSV-1 TK(Q125N) gene compared with osteosarcoma cells expressing wild-type HSV-1 TK. BVDU monophosphate accumulation gave rise to a much greater inhibition of cellular thymidylate synthase in HSV-1 TK(Q125N) gene-transfected cells than wild-type HSV-1 TK gene-transfected osteosarcoma tumor cells without significantly changing the cytostatic potency of BVDU for the HSV-1 TK gene-transfected tumor cells. Accordingly, the presence of the Q125N mutation in HSV-1 TK gene-transfected tumor cells was found to result in a multilog decrease in the cytostatic activity of those pyrimidine nucleoside analogs that in their monophosphate form do not have marked affinity for thymidylate synthase [i.e., 1-beta-D-arabinofuranosylthymine and (E)-5-(2-bromovinyl)-1-beta-D-arabinofuranosyluracil].

Amino Acid Substitution↗
PubMed2001

Exploitation of the low fidelity of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase and the nucleotide composition bias in the HIV-1 genome to alter the drug resistance development of HIV.

The RNA genome of the lentivirus human immunodeficiency virus type 1 (HIV-1) is significantly richer in adenine nucleotides than the statistically equal distribution of the four different nucleotides that is expected. This compositional bias may be due to the guanine-to-adenine (G-->A) nucleotide hypermutation of the HIV genome, which has been explained by dCTP pool imbalances during reverse transcription. The adenine nucleotide bias together with the poor fidelity of HIV-1 reverse transcriptase markedly enhances the genetic variation of HIV and may be responsible for the rapid emergence of drug-resistant HIV-1 strains. We have now attempted to counteract the normal mutational pattern of HIV-1 in response to anti-HIV-1 drugs by altering the endogenous deoxynucleoside triphosphate pool ratios with antimetabolites in virus-infected cell cultures. We showed that administration of these antimetabolic compounds resulted in an altered drug resistance pattern due to the reversal of the predominant mutational flow of HIV (G-->A) to an adenine-to-guanine (A-->G) nucleotide pattern in the intact HIV-1-infected lymphocyte cultures. Forcing the virus to change its inherent nucleotide bias may lead to better control of viral drug resistance development.

Anti-HIV Agents↗
PubMed2001

Furano pyrimidines as novel potent and selective anti-VZV agents.

Bicyclic furano pyrimidine nucleosides have been found to be highly potent and selective inhibitors of varicella zoster virus (VZV). They are inactive against herpes simplex virus and have been known for several decades as (unwanted) synthetic by-products in the Pd-catalysed coupling of acetylenes to 5-iodo nucleosides. These fluorescent bicyclic nucleosides are now established as a new family of potent antivirals. They are unusual in that they exhibit complete specificity for VZV and require an alkyl (or alkylaryl) side-chain for biological activity. The latter requirement confers extremely high lipophilicities on these compounds, unknown amongst chemotherapeutic nucleosides, which may be of considerable importance in formulation, dosing and tissue distribution. The most potent compounds reported are p-alkylaryl compounds, with EC50 values below 1 nM versus VZV and selectivity index values of around 1,000,000. Here, we review the discovery, synthesis, characterization, antiviral profile, SAR, mechanism of action and development prospects for this new family of antivirals.

Antiviral Agents↗
PubMed2001

5'-Nor carbocyclic 5'-deoxy-5'-(isobutylthio)adenosine and a 2',3'-dideoxy-2',3'-didehydro derivative.

The inhibition of biochemical processes requiring S-adenosylmethionine as a co-factor have led to many nucleoside-based medicinal agents. Included in this group are 5'-deoxy-5'-(isobutylthio)adenosine (SIBA), a nucleoside with antiparasitic, antiviral and antiproliferative effects, and 5'-noraristeromycin, a carbocyclic-derived nucleoside with potent antiviral properties. This report brings together the structural components of these two compounds by describing both enantiomers of carbocyclic 5-nor SIBA (3 and 4). Owing to the recent interest in 2',3'-dideoxy-2',3'-didehydro nucleosides as antiviral agents, this derivative of 3 (5) is also described. All three compounds were screened against a variety of viruses and were found to be inactive at high concentrations or at limiting concentrations for the screening methods. The viruses subjected to 3-5 were herpes simplex virus types 1 and 2, human cytomegalovirus, vaccinia virus, vesicular stomatitis virus, respiratory syncytial virus, varicelIa zoster virus, coxsackie virus, parainfluenza-3 virus, sindbis virus, punta toro virus, reovirus-1, human immunodeficiency virus, influenza virus types A and B, adenovirus type 1 and measles virus. These results suggest that the C-5' methylene of the C-5' thio-based carbocyclic nucleosides is important for their antiviral properties.

Adenosine↗
PubMed2001

Synthesis, biological activity, pharmacokinetic properties and molecular modelling studies of novel 1H,3H-oxazolo[3,4-a]benzimidazoles: non-nucleoside HIV-1 reverse transcriptase inhibitors.

New 1H,3H-oxazolo[3,4-albenzimidazoles (OBZs) were synthesized as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTI) to extend the structure-activity relationships observed for an early series of related 1H,3H-thiazolo[3,4-a]benzimidazole derivatives (TBZs). The new compounds showed inhibitory activity against the replication of various HIV-1 strains, including NNRTI-resistant strains. Testing of a representative OBZ derivative in an HPLC assay on biological fluids, indicated that the sulphur substitution appreciably improved the metabolic stability of the TBZ compound. In addition, molecular modelling studies demonstrated that OBZs, TBZs and other NNRTIs have similar structural properties, that is a butterfly-like conformation, which is a key structural requirement for reverse transcriptase inhibition.

Animals↗
PubMed2001

Bicyclic nucleoside inhibitors of varicella-zoster virus (VZV): Pd-catalysed synthesis of 5-aryl derivatives and their biological evaluation.

We have recently reported the discovery of an entirely new category of potent antiviral agents based on novel deoxynucleoside analogues with unusual fluorescent bicyclic furano base moieties. In order to probe structure activity relationships we prepared a series of 5-aryl derivatives of the lead structures. We herein report the synthesis, characterization, and antiviral evaluation of these novel compounds. 5-Aryl derivatives of the parent nucleosides were synthesized from the corresponding alkynyl deoxyuridines using a simple, versatile and efficient one-step conversion, based on a palladium-catalysed cyclization. As previously noted for the lead compounds, a long alkyl side-chain on the base moiety is essential for antiviral activity. Even with the optimal (C8-C10) side-chain, most of the present compounds are markedly less active than their parent structures. However, some of the synthesized compounds still retained antiviral activity at non-cytotoxic concentrations, being only two- to fivefold less active than the current clinical agent acyclovir. Possible reasons for this structure activity relationship are discussed.

Acyclovir↗
PubMed2001

Synthesis and antiviral evaluation of phosphoramidate derivatives of (E)-5-(2-bromovinyl)-2'-deoxyuridine.

We report the design, synthesis and antiviral evaluation of a number of lipophilic, masked phosphoramidate derivatives of the antiherpetic agent (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU), designed to act as membrane soluble prodrugs of the free nucleotide. The phosphoramidate derivatives of BVDU that contain L-alanine exhibited potent anti herpes simplex virus type 1 and varicella-zoster virus activity but lost marked activity against thymidine kinase-deficient virus strains. The phosphoramidate derivative bearing the amino acid alpha,alpha-dimethylglycine showed poor activity in all cell lines tested. It appears that successful kinase bypass by phosphoramidates is highly dependent on the nucleoside analogue, amino acid and ester structure, as well as the cell line to which the drugs are exposed.

Acyclovir↗
PubMed2001

Antiviral activity of cyclosaligenyl prodrugs of acyclovir, carbovir and abacavir.

The cyclosaligenyl (cycloSal) derivatives of the monophosphates of three acyclic or carbocyclic guanosine analogues, for example, acyclovir (ACV), carbovir (CBV) and abacavir (ABC), were investigated for their activity against retrovirus (HIV, Moloney sarcoma virus) and herpes simplex virus (HSV) activity in cell culture. The extent of the antiviral potency of the prodrugs depended on the nature of the nucleoside, the substituent on the cycloSal moiety and the virus investigated. Most notably, and unlike the parent compound ACV, cycloSal-ACV monophosphate (MP) prodrugs retained pronounced activity against ACV-resistant (thymidine kinase-deficient) HSV-1 and also gained anti-HIV activity. While the cycloSal-CBVMP prodrugs did not show enhanced activity compared with the parent compound CBV, the cycloSal-ABCMP prodrugs afforded markedly increased potency against both HSV and HIV. Our data indicate that the cycloSal prodrug approach can be useful to deliver directly the MP derivatives of nucleoside analogues into the intact, virus-infected cells, thus improving and extending the antiviral potency and spectrum of the drugs against retro- and herpesvirus strains.

Acyclovir↗
PubMed2001

In vitro activity of polyhydroxycarboxylates against herpesviruses and HIV.

The antiviral activity of 17 polyhydroxycarboxylates derived from phenolic compounds was evaluated against herpesviruses and HIV. When present during virus adsorption several of the polymers exhibited potent activity against herpes simplex virus type 1 (HSV-1), HSV-2, thymidine kinase deficient HSV-1, human cytomegalovirus (HCMV) and HIV-1 and HIV-2 at concentrations that were not toxic to the host cells. A close correlation was found between the 50% inhibitory concentrations of the polyhydroxycarboxylates against HCMV-induced cytopathicity, their inhibitory effect on the expression of HCMV-specific immediate early antigens and their inhibitory effects on HCMV adsorption to the cells. The antiviral activity of the phenolic polymers was dependent on the presence of a sufficient number of carboxylic groups. The mechanism of antiviral action of the polyhydroxycarboxylates can thus be ascribed to inhibition of virus adsorption. This type of compound may have potential in a vaginal gel to prevent sexual transmission of HSV and HIV.

Antiviral Agents↗
PubMed2001

Anti-HIV-1 activity of benzothiadiazine dioxide.

Antiviral assays carried out on the potent benzothiadiazine dioxide (BTD) human cytomegalovirus (HCMV) inhibitors have led us to find marginal but selective anti-HIV-1 activity. Specific pharmacological studies, such as time of addition experiments and assays on specific viral strains with mutations on its reverse transcriptase, have indicated that BTD compounds act as non-nucleoside reverse transcriptase inhibitors. Theoretical calculations showed a butterfly conformation for the active derivatives that are compatible with their mechanism of action. Therefore, BTD derivatives can be considered as potential lead compounds for the treatment of opportunistic HCMV infections in immunocompromised individuals such as AIDS patients.

Antiviral Agents↗
PubMed2001

Solid state properties of pure UC-781 and solid dispersions with polyvinylpyrrolidone (PVP K30).

The purpose of this study was to elucidate the physical structure of solid dispersions of the antiviral agent UC-781 (N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-furancarbothioamide) with polyvinylpyrrolidone (PVP K30). Solid dispersions were prepared by coevaporating UC-781 with PVP K30 from dichloromethane. The physicochemical properties of the dispersions were evaluated in comparison with the physical mixtures by differential scanning calorimetry (DSC), X-ray powder diffraction, and FT-IR spectroscopy. We investigated the single crystal structure of pure UC-781. The data from single crystal analysis showed that UC-781 crystallized with orthorhombic symmetry in the space group Pcab. Its cell parameters were found to be; a = 8.1556(7) A,b = 17.658(2) A and c = 23.609(2) A; the unit cell was made up of eight molecules of UC-781. The molecules formed intermolecular hydrogen bonds between NH and thio groups, and were packed in a herringbone-like structure. The data from X-ray powder diffraction showed that crystalline UC-781 was changed into the amorphous state by co-evaporating it with PVP K30. From differential scanning calorimetry analysis, UC-781 peaks were observed in the DSC curves of all physical mixtures, while no peaks corresponding to the drug could be observed in the solid dispersions with the same drug composition up to the concentration of 50% w/w. The data from FT-IR spectroscopy showed the distortions and disappearance of some bands from the drug, while other bands were too broad or significantly less intense compared with the physical mixtures of the crystalline drug in PVP K30. Furthermore, the results from IR spectroscopy demonstrated that UC-781 interacted with PVP K30 in solid dispersions through intermolecular H-bonding.

Anilides↗
PubMed2001

Novel carbocyclic nucleosides containing a cyclobutyl ring: adenosine analogues.

(1S,1'R)-cis-1-(3'-aminomethyl-2',2'-dimethylcyclobutyl)ethanol (1) and (1S,1'R)-cis-1-[3'-(2-aminoethyl)-2',2'-dimethylcyclobutyl]ethanol (2) were used as precursors in the synthesis of cyclobutyl nucleoside analogues containing adenine and 8-azaadenine moieties, which were tested as antiviral and antitumoral agents in a variety of assay systems. Compounds 8 and 9 displayed significant activity against respiratory syncytial virus, and compounds 14 and 15 were moderately active against vaccinia virus.

Adenosine↗
PubMed2001

3-Benzamido, ureido and thioureidoimidazo[1,2-a]pyridine derivatives as potential antiviral agents.

This work reports the synthesis and the antiviral activities of 3-benzamido, 3-phenylureido and 3-phenylthioureido derivatives in the imidazo[1,2-a]pyridine series. The structure was proven by NMR spectroscopy. The synthesized compounds were evaluated against a large number of viruses. The 3-phenylthioureido derivative 7 showed moderate activity against human cytomegalovirus (HCMV) in vitro. The crystallographic data for 8 are also reported and explain the absence of activity against human immunodeficiency virus (HIV).

Anti-HIV Agents↗
PubMed2000

Highly potent and selective inhibition of varicella-zoster virus by bicyclic furopyrimidine nucleosides bearing an aryl side chain.

In addition to our recent report on the potent anti-varicella-zoster virus (VZV) activity of some unusual bicyclic furopyrimidine nucleosides bearing long alkyl side chains, we herein report the further significant enhancement of the antiviral potency by inclusion of a phenyl group in the side chain of these compounds. The target structures were prepared by the Pd-catalyzed coupling of a series of para-substituted arylacetylenes with 5-iodo-2'-deoxyuridine, to give intermediate 5-alkynyl nucleosides which were cyclized in the presence of Cu to give the desired bicyclic systems. The compounds display extraordinary potency and selectivity for VZV; the most active are ca. 10 000 times more potent than the reference compound acyclovir and ca. 100 times more potent than the alkyl analogues earlier reported by us. The current compounds show little cytotoxicity, leading to selectivity index values >/= 1 000 000. From a range of DNA and RNA viruses tested, only VZV was inhibited by these compounds indicating their extreme selectivity for this target virus. The novelty of the molecules, coupled with their extreme potency and selectivity, their desirable physicochemical properties, and their relative ease of synthesis, makes them of considerable interest for potential drug development for VZV infections.

Antiviral Agents↗
PubMed2000

Synthesis and antitumor activities of novel pyrimidine derivatives of 2,3-O,O-dibenzyl-6-deoxy-L-ascorbic acid and 4,5-didehydro-5,6- dideoxy-L-ascorbic acid.

The new pyrimidine derivatives of 2,3-O, O-dibenzyl-6-deoxy-L-ascorbic acid (8-10) were synthesized by condensation of uracil and its 5-fluoro- and 5-trifluoromethyl-substituted derivatives with 4-(5,6-epoxypropyl)-2, 3-O,O-dibenzyl-L-ascorbic acid (7), while pyrimidine derivatives of 4,5-didehydro-5,6-dideoxy-L-ascorbic acid (14-17) with free C-2' and C-3' hydroxy groups in the lactone ring were obtained by debenzylation of 11-13 with boron trichloride. Z-Configuration of the C4'=C5' double bond and position of the benzyl group in the lactone ring of 14 were deduced from their (1)H and (13)C NMR spectra and connectivities in COSY, ROESY, and HMBC spectra. The exact stereostructure of 13 was confirmed by its X-ray crystal structure analysis. Of all the compounds in the series, compound 16 containing a 5-fluoro-substituted uracil ring showed the most significant antitumor activities against murine leukemia L1210/0 (IC(50) = 1.4 microg/mL), murine mammary carcinoma FM3A/0 (IC(50) = 0.78 microg/mL), and, to a lesser extent, human T-lymphocyte cells Molt4/C8 (IC(50) = 31.8 microg/mL) and CEM/0 cell lines (IC(50) = 20.9 microg/mL).

Animals↗