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Biomedical subjects

J Balzarini

Publications and source records attributed to J Balzarini.

At least 451 records · Page 25Linked to original sources
PubMed1987

Antiviral activity of phosphonylmethoxyalkyl derivatives of purine and pyrimidines.

Various 3-hydroxy-2-phosphonylmethoxypropyl (HPMP) and 2-phosphonylmethoxyethyl (PME) derivatives of purine [adenine (A), guanine (G), 2,6-diaminopurine (DAP), 2-monoaminopurine (MAP), hypoxanthine (HX)] and pyrimidine [cytosine (C), uracil (U), thymine (T)] have been evaluated for their antiviral properties. PMEDAP, (S)-HPMPA [and the cyclic phosphonate thereof, (S)-cHPMPA)], (S)-HPMPC, PMEG, PMEA, HPMPG and HPMPDAP proved to be effective inhibitors of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2). (S)-HPMPA and (S)-cHPMPA were the most effective inhibitors of varicella-zoster virus (VZV), and (S)-HPMPC was the most effective inhibitor of cytomegalovirus (CMV). Against adenovirus (types 2, 3 and 4) and vaccinia virus again (S)-HPMPA and (S)-cHPMPA showed the greatest inhibitory activity. As a rule, the PME derivates were much less inhibitory to VZV, CMV, vaccinia and adenovirus than the HPMP derivatives. However, PMEA, PMEDAP and PMEMAP showed marked and selective activity against the human immunodeficiency virus (HIV). (S)-HPMPA was selected for further evaluation in animal model infections. It proved efficacious in the topical treatment of HSV-1 keratitis in rabbits and cutaneous HSV-1 infection in hairless mice, and in the systemic treatment of both HSV-1 and vaccinia virus infections in mice.

Animals↗
PubMed1987

5-Quinone derivatives of 2'-deoxyuridine 5'-phosphate: inhibition and inactivation of thymidylate synthase, antitumor cell, and antiviral studies.

Both photochemical aromatic substitution and palladium (0)-catalyzed biaryl coupling reactions have been employed in the synthesis of 5-substituted 2'-deoxyuridines. The former procedure was useful in the preparation of the 3,4-dimethyl-2,5-dimethoxyphenyl derivative 12a and the 3,4,6-trimethyl-2,5-dimethoxyphenyl derivative 12b. The latter reaction was efficient in the preparation of the 2-(3-methyl-1,4-dimethoxynaphthyl) derivative 14. These compounds and their nucleotides (20a-c) were converted to the corresponding quinone nucleosides 19a-c and nucleotides 6-8 by an oxidative demethylation reaction using ceric ammonium nitrate and silver(II) oxide, respectively. The kinetics and products of the reaction of the quinone nucleosides 19a,b with methyl thioglycolate showed rapid addition to the quinone ring in the trisubstituted derivative 19a and somewhat slower redox reactions with the tetrasubstituted quinones 19b and 19c. All six nucleotides had high affinity for the title enzyme from Lactobacillus casei with Ki values ranging from 0.59 to 3.6 microM; the most effective compounds were the dimethyl quinone 6 and the naphthoquinone 8. Somewhat higher inhibitory constants were observed with the quinones against the L1210 enzyme. The dimethyl quinone nucleotide 6 showed time-dependent inactivation (kinact = 0.015 s-1) against the L. casei enzyme, a rate saturation effect, and substrate protection in accord with the kinetic expression for an active-site-directed alkylating agent. The apparent second-order rate of this reaction (2.5 X 10(4) M-1 s-1) is one-twentieth the rate (kcat.) of the normal enzymatic reaction leading to product. None of the compound exhibited sufficient activity in the antitumor cell or antiviral assays to warrant further study.

Animals↗
PubMed1987

Nucleic acid related compounds. 51. Synthesis and biological properties of sugar-modified analogues of the nucleoside antibiotics tubercidin, toyocamycin, sangivamycin, and formycin.

Treatment of 7-amino-3-beta-D-ribofuranosylpyrazolo[4,3-d]pyrimidine (formycin) with alpha-acetoxyisobutyryl bromide followed by deprotection of the resulting trans-vicinal acetoxy bromides and hydrogenolysis of the separated bromohydrins gave 2'-deoxy-(23%) and 3'-deoxyformycin (32%) after complete deprotection and purification of their hydrochloride salts. An analogous sequence gave 3'-deoxytoyocamycin and/or 3'-deoxysangivamycin in approximately 80% yields from toyocamycin. Antiviral, antineoplastic, and antimetabolic effects were evaluated for the formycin compounds and 4-amino-7-beta-D-ribofuranosylpyrrolo[2,3-d]pyrimidine (tubercidin), its 5-cyano- (toyocamycin), and 5-carbamoyl-(sangivamycin) antibiotic congeners in comparison with their 2'-deoxy, 3'-deoxy, and arabino analogues. In all cases, the modified-sugar compounds were less cytotoxic than the parent antibiotics. The majority also exhibited lower antiviral potency. However, the xylo-tubercidin analogue retained potent antiherpes 1 and 2 activity with decreased cytotoxicity. Labeled metabolite studies suggested that effects of these compounds on RNA and/or protein synthesis might be more significant than interference with DNA synthesis.

Animals↗
PubMed1987

3'-substituted 2',3'-dideoxynucleoside analogues as potential anti-HIV (HTLV-III/LAV) agents.

A series of 2',3'-unsaturated and 3'-substituted 2',3'-dideoxynucleoside analogues of purines and pyrimidines have been synthesized and evaluated for their inhibitory activity against human immunodeficiency virus (HIV). The 2',3'-unsaturated analogues of 2',3'-dideoxycytidine (ddeCyd) and 2',3'-dideoxythymidine (ddeThd), 3'-azido-2',3'-dideoxythymidine (AzddThd), 3'-fluoro-2',3'-dideoxythymidine, 2',3'-dideoxycytidine (ddCyd), and 2',3'-dideoxyadenosine (ddAdo) emerged as the most potent inhibitors of HIV-induced cytopathogenicity in the human T lymphocyte cell lines ATH8 and MT4. In ATH8 cells ddCyd, ddeCyd, and ddAdo had the highest therapeutic index whereas in MT4 cells AzddThd, ddThd, ddCyd, and ddAdo were the most selective. Derivatives from ddThd in which the substituent group was linked to the 3'-carbon atom via a thio, sulfonyl, or oxygen bridge were far less inhibitory to HIV than was AzddThd.

Antiviral Agents↗
PubMed1987

Synthesis and anti-HIV activity of various 2'- and 3'-substituted 2',3'-dideoxyadenosines: a structure-activity analysis.

A systematic synthesis was undertaken of 2',3'-dideoxyadenosine analogues with either an azido, fluorine, or hydroxyl group substituted in the "up" or "down" position of C-2 or C-3 of the sugar moiety. The compounds were evaluated against the cytopathogenicity of human immunodeficiency virus (HIV) for MT-4 cells. The four azido derivatives 6, 7, 8, and 9 were synthesized by a nucleophilic displacement reaction with lithium azide on the mesylates 3, 2, 5, and 4. (Diethylamido)sulfur trifluoride was used for the synthesis of 10-12. The compound 13 was obtained by 2'-deoxygenation of 9-(3-fluoro-3-deoxy-beta-D-xylofuranosyl)adenine. Among the azido derivatives, compound 8 with the 3'-azido "down" was slightly more active than 2',3'-dideoxyadenosine (1) but considerably more toxic, and, of the fluorine series, compound 11, with the 2'-fluoro "up", was the most selective inhibitor of HIV, although it was less active than 1. Hence, none of the newly synthesized compounds proved more selective in their anti-HIV activity than the parent compound, 1.

Antiviral Agents↗
PubMed1987

Ribavirin antagonizes inhibitory effects of pyrimidine 2',3'-dideoxynucleosides but enhances inhibitory effects of purine 2',3'-dideoxynucleosides on replication of human immunodeficiency virus in vitro.

The combined antiviral effects of various 2',3'-dideoxynucleosides and ribavirin on the replication of human immunodeficiency virus type 1 in MT-4 cells have been examined. Ribavirin antagonized the antiviral activity of the pyrimidine 2',3'-dideoxynucleosides (3'-azido-2',3'-dideoxythymidine, 2',3'-dideoxythymidin-2'-ene, 2',3'-dideoxycytidine, and 2',3'-dideoxycytidin-2'-ene), but enhanced the antiviral activity of the purine 2',3'-dideoxynucleosides (2',3'-dideoxyadenosine and 2',3'-dideoxyguanosine). Combinations of the 2',3'-dideoxynucleosides with each other were also examined. These combinations resulted in an additive to subsynergistic effect.

Cytopathogenic Effect, Viral↗
PubMed1987

Thymidylate synthase is the principal target enzyme for the cytostatic activity of (E)-5-(2-bromovinyl)-2'-deoxyuridine against murine mammary carcinoma (FM3A) cells transformed with the herpes simplex virus type 1 or type 2 thymidine kinase gene.

Murine mammary carcinoma FM3A cells, deficient in cytosol thymidine (dThd) kinase (TK) activity and transformed by the herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2) TK gene (designated FM3A TK-/HSV-1 TK+ and FM3A TK-/HSV-2 TK+, respectively) proved extremely sensitive to the cytostatic action of the potent antiherpetic drugs (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and (E)-5-(2-iodovinyl)-2'-deoxyuridine (IVDU). The fact that FM3A TK-/HSV-2 TK+ cells were 5-fold more sensitive to the cytostatic action of BVDU and IVDU but incorporated [125I]IVDU to a 20-fold lower extent into their DNA than did FM3A TK-/HSV-1 TK+ cells led us to conclude that incorporation of these compounds into DNA of HSV TK gene-transformed cell lines is not directly related to their cytostatic action. In attempts to unravel the mechanism of the cytostatic effects of BVDU and IVDU on HSV TK gene-transformed FM3A cells, both compounds were submitted to an intensive biochemical study. Thymidylate synthase was identified as the principal target enzyme for the cytostatic action of BVDU and IVDU since (i) both compounds were far more inhibitory to 2(1)-deoxyuridine (dUrd) than to dThd incorporation into HSV TK gene-transformed FM3A cell DNA, (ii) the cytostatic action of BVDU and IVDU was more readily reversed by dThd than by dUrd, (iii) both compounds strongly inhibited the metabolic pathway leading to the incorporation of 2'-deoxycytidine (dCyd) into DNA thymidylate, (iv) BVDU and IVDU strongly inhibited tritium release from [5-3H]dCyd and [5-3H]dUrd in intact HSV TK gene-transformed FM3A cells, and (v) [125I]IVDU accumulated intracellularly as its 5'-monophosphate to concentration levels considerably higher than those required to inhibit partially purified thymidylate synthase. The inhibitory effects mentioned under (i) to (iv) were not observed with the parental FM3A/0 and FM3A/TK- cells; they were more pronounced for FM3A TK-/HSV-2 TK+ cells than for FM3A TK-/HSV-1 TK+ cells, which correlates with the differential cytostatic effects of BVDU and IVDU on these cells.

Animals↗
PubMed1987

Differential affinities of pyrimidine nucleoside analogues for deoxythymidine and deoxycytidine kinase determine their incorporation into murine leukemia L1210 cells.

A number of 5-substituted pyrimidine deoxyribonucleoside (dThd or dCyd) derivatives have been evaluated for their effects on the incorporation of dThd and dCyd into the nucleotide pool and nucleic acids of murine leukemia L1210 cells. Several observations indicate that the dThd kinase and dCyd kinase activity of the cells and the differential affinities of these enzymes for the pyrimidine deoxyribonucleosides determine the incorporation of dThd and dCyd into the cells: (i) dThd and dCyd were not incorporated into mutant L1210 cells deficient in either dThd kinase or dCyd kinase activity; (ii) for a series of 5-substituted dThd and dCyd analogues a strong correlation was found between their inhibitory effects on the incorporation of dThd or dCyd into cell material and their Ki/Km for dThd kinase and dCyd kinase (r = 0.92 and 0.97, respectively); (iii) inhibitors of DNA synthesis (i.e. araC) and RNA synthesis (i.e. actinomycin D) suppressed the incorporation of dThd, most likely due to an inhibitory activity at the dThd kinase level (through the allosteric action of dTTP or slow regeneration of dThd kinase).

Animals↗
PubMed1987

2',3'-Dideoxycytidine: regulation of its metabolism and anti-retroviral potency by natural pyrimidine nucleosides and by inhibitors of pyrimidine nucleotide synthesis.

The antiretroviral action of 2',3'-dideoxycytidine (ddCyd) depends on its intracellular conversion to the 5'-triphosphate metabolite ddCTP. The effect of natural pyrimidines and pyrimidine nucleosides, as well as of a number of inhibitors of pyrimidine nucleotide synthesis (i.e., N-(phosphonacetyl)-L-aspartate, 6-azauridine, pyrazofurin, 3-deazauridine, and hydroxyurea) on the metabolism of the potent anti-human immunodeficiency virus drug ddCyd has been investigated in human and murine cell lines. Deoxycytidine (dCyd) and cytidine (Cyd) effectively blocked the intracellular phosphorylation of ddCyd: dCyd by competition with ddCyd for 2'-deoxycytidine kinase, and Cyd probably by competition with the higher nucleoside mono- and diphosphate kinases. These conclusions are supported by the observations that (i) the cytostatic effects of ddCyd against human Molt/4F cells are significantly reversed by dCyd; (ii) the antiviral effects of ddCyd against hman immunodeficiency virus-infected human ATH8 cells are reversed by dCyd and Cyd; (iii) phosphorylated metabolites of ddCyd could not be detected in a 2'-deoxycytidine kinase-deficient murine leukemia (L1210)/araC cell line; and (iv) ddCyd lacked any cytostatic effect against this araC-resistant L1210 cell line. In contrast to dCyd and Cyd, thymidine (dThd) stimulated formation of phosphorylated ddCyd metabolites. The degree of this stimulation proved dependent on preincubation time and dThd concentration. There was a correlation between the increased ddCTP levels upon preincubation of the cells with dThd, and decreased dCyd-5'-triphosphate pools, presumably caused by inhibition of cytidine-5' -diphosphate reductase by dThd-5'-triphosphate. In an attempt to discover compounds other than dThd that are able to stimulate ddCTP formation, a number of inhibitors of pyrimidine nucleotide metabolism were also studied. Under our experimental conditions, 3-deazauridine and hydroxyurea proved equally as effective as dThd in stimulating ddCyd phosphorylation. Finally, we could demonstrate that dThd significantly enhanced the protective effect of ddCyd against human immunodeficiency virus-infected ATH8 cells.

Animals↗
PubMed1987

The anti-HTLV-III (anti-HIV) and cytotoxic activity of 2',3'-didehydro-2',3'-dideoxyribonucleosides: a comparison with their parental 2',3'-dideoxyribonucleosides.

A series of 2',3'-didehydro-2',3'-dideoxyribonucleosides (ddeNs) [i.e., 2',3'-dideoxythymidinene (ddeThd), 2',3'-dideoxyuridinene (ddeUrd), 2',3'-dideoxycytidinene (ddeCyd), and 2',3'-dideoxyadenosinene (ddeAdo)] has been synthesized and the individual members compared in terms of their in vitro antiviral, antimetabolic, and cytostatic properties to their 2',3'-saturated counterparts (ddNs) (i.e., ddThd, ddUrd, ddCyd and ddAdo). All ddeNs except ddeUrd are potent and/or selective inhibitors of human immunodeficiency virus (HIV) in vitro, ddeCyd being the most potent (MIC50, 0.30 microM). The inhibitory effect of ddeCyd on ATH8 cell proliferation and HIV-induced cytopathogenicity is comparable to that of ddCyd. ddeThd is a more potent anti-HIV agent than ddThd (MIC50, 3.4 microM and 84 microM, respectively), but also more cytostatic (ID50, 172 microM and greater than 2000 microM, respectively). However, its in vitro chemotherapeutic index is higher than that of 3'-azido-2',3'-dideoxythymidine, a drug which has recently proven effective in the treatment of acquired immunodeficiency syndrome. ddeAdo has a weaker anti-HIV and a stronger cytostatic effect than ddAdo. Neither ddeUrd nor ddUrd shows significant anti-retroviral activity at 500 microM. In contrast to their anti-retroviral activity, both ddNs and ddeNs lack any appreciable inhibitory activity against a series of nononcogenic RNA and DNA viruses, pointing to their selectivity as anti-retroviral agents. All ddeNs show a progressive loss of anti-retroviral effect upon prolonged incubation with virus-infected cells. This phenomenon is most likely due to the chemical instability of these compounds, and not to a preferential enzymatic phosphorolytic cleavage of the ddeNs. Evidence is presented that ddeCyd and ddCyd, and ddeThd and ddThd are phosphorylated by cellular dCyd kinase and dThd kinase, respectively. However, the Ki values as alternate substrate inhibitors for their respective kinases are high (greater than 500 microM), indicating poor substrate activity and, thus, poor anabolism in ATH8 cells.

Animals↗
PubMed1986

Potent and selective anti-HTLV-III/LAV activity of 2',3'-dideoxycytidinene, the 2',3'-unsaturated derivative of 2',3'-dideoxycytidine.

2',3'-Dideoxycytidinene (ddeCyd), the 2',3'-unsaturated derivative of 2',3'-dideoxycytidine (ddCyd) is, like ddCyd itself, a potent and selective inhibitor of HTLV-III/LAV in vitro. This conclusion is based on the relatively high ratio of effective antiviral dose (0.3 microM) versus cell growth inhibitory concentration (20-35 microM) and the lack of any appreciable inhibitory activity against a series of non-oncogenic RNA and DNA viruses. Both compounds were considerably more inhibitory to human lymphoid cell lines than human nonlymphoid or murine cell lines. They were highly dependent on prior activation by deoxycytidine kinase to exert their anti-HTLV-III/LAV and cytostatic effects. In contrast with ddCyd, ddeCyd lost part of its anti-retrovirus effect upon prolonged incubation (10 days) with the virus-infected cells in culture.

Animals↗
PubMed1986

Aurintricarboxylic acid and Evans Blue represent two different classes of anionic compounds which selectively inhibit the cytopathogenicity of human T-cell lymphotropic virus type III/lymphadenopathy-associated virus.

Aurintricarboxylic acid, an anionic triphenylmethane dye, and Evans Blue, an anionic compound structurally related to suramin, are, like suramin itself, inhibitors of human T-cell lymphotropic virus type III (HTLV-III)/-lymphadenopathy-associated virus (LAV) in vitro. These compounds may be targeted, at least in part, at the HTLV-III/LAV reverse transcriptase. The lack of any appreciable cytostatic action of aurintricarboxylic acid, Evans Blue and suramin against several murine and human cell lines, their inability to inhibit cellular DNA, RNA and protein synthesis, and their high lethal dose-50 (greater than or equal to 0.340 g/kg) for NMRI mice point to the selectivity of the compounds as inhibitors of HTLV-III/LAV.

Animals↗
PubMed1986

Comparative inhibitory effects of suramin and other selected compounds on the infectivity and replication of human T-cell lymphotropic virus (HTLV-III)/lymphadenopathy-associated virus (LAV).

Suramin and various other selected compounds were evaluated for their in vitro inhibitory effects on the infectivity and replication of human T-cell lymphotropic virus (HTLV/III)/lymphadenopathy-associated virus (LAV). As parameters for infectivity and replication, respectively, we followed the cytopathic effect of HTLV-III/LAV on ATH 8 cells, a T-cell clone with high susceptibility to HTLV-III/LAV, and the expression of HTLV-III/LAV p24 gag protein in H9 cells infected with HTLV-III/LAV. As the most effective inhibitors of HTLV-III/LAV the following substances emerged (in order of decreasing activity): Evans Blue approximately equal to suramin greater than phosphonoformic acid greater than Direct Yellow 50. Several purine nucleoside analogues including vidarabine, tubercidin, neplanocin A, dihydroxypropyladenine, pyrazofurin and ribavirin were not inhibitory to HTLV-III/LAV. In our test systems, involving a high multiplicity of infection, HPA-23, previously reported to be effective against LAV reverse transcriptase, showed no inhibitory effect on HTLV-III/LAV infectivity for ATH 8 cells and proved only weakly inhibitory to HTLV-III/LAV replication in H9 cells. Thus, among the anionic dyes that are structurally related to suramin, compounds were found which were as active as suramin itself, if not more so.

Animals↗
PubMed1986

Synthesis, structure, and antitumor and antiviral activities of a series of 5-halouridine cyclic 3',5'-monophosphates.

A series of potential prodrug 5-halouridine 3',5'-cyclic monophosphates (5-X-cUMPs, X = F, Cl, Br, I, 1-4) has been prepared and tested for antitumor activity against murine leukemia L1210/0 and human lymphoblast Raji/0 cells and their deoxythymidine kinase deficient (TK-) counterparts, as well as for antiviral activity in primary rabbit kidney cells infected with herpes simplex virus type 1 or 2, vaccinia virus, or vesicular stomatitis virus. The 5-halopyrimidine bases, nucleosides (5-X-U), and 5'-monophosphates (5-X-UMP) were tested for comparison. 5-F-cUMP (1) showed reasonably potent inhibition of tumor cell proliferation (ID50 = 0.33-1.6 micrograms/mL), while the remaining diesters displayed ID50's ranging from 210 to greater than 1000 micrograms/mL. 5-F-cUMP was 70- to 300-fold less active than 5-F-dU in the same systems. With TK- L1210 cells, 5-F-cUMP was as potent as with the normal (L1210/0) line but was about fourfold less active with TK- Raji cells compared to Raji/0 cells. The 5-X-cUMPs showed little potency as antivirals. A single-crystal X-ray analysis of the ammonium salt of 5-I-cUMP confirmed its structure and showed the conformation of the phosphate ring to be the expected chair. The ribose pucker is near 3(4)T, and the torsion angle about the beta-glycosidic N(1)-C(1') bond is in the syn range (-84.8 degrees).

Animals↗
PubMed1986

Synthesis and antitumor and antiviral properties of 5-alkyl-2'-deoxyuridines, 3',5'-cyclic monophosphates, and neutral cyclic triesters.

A series of 5-alkyl-2'-deoxyuridine 3',5'-cyclic monophosphates (5-R-cdUMP's, R = Et, i-Pr, n-Pr, n-Bu, n-Pent, n-Hex, n-Oct) was prepared and tested in culture systems as antitumor and antiviral agents in comparison to the 5-alkyl-2'-deoxyuridines (5-R-dUrd's) themselves. Only the 5-Et- and 5-n-Bu-cdUMP showed appreciable cytostatic activities against murine L1210 and human lymphoblast Raji cells (ID50 range: 28-82 micrograms/mL). 5-Et-dUrd itself was much more active (ID50 = 1.6 and 2.9 micrograms/mL). The 5-i-Pr-, and 5-n-Bu-dUrd's were inactive, but activity increased again for groups with chain lengths of five carbons or greater. 5-Et-cdUMP and 5-Et-dUrd had greatly reduced activities against deoxythymidine kinase deficient (TK-) L1210 and Raji cells. 5-Et-cdUMP evidently is not an efficient prodrug source of the corresponding 5'-monophosphate where the TK- cells are concerned. Of the 5-R-cdUMP's, 5-Et-cdUMP displayed reasonably good antiviral potency against herpes simplex types 1 and 2 (MIC50, mostly 7-70 micrograms/mL) and vaccinia virus (MIC, 70 micrograms/mL). The activity was nonetheless 10- to 100-fold less than that for 5-Et-dUrd. The other 5-R-dUrd's generally showed decreasing antiviral activity with increasing 5-R chain length. Methyl and/or benzyl neutral triesters of certain 5-R-cdUMP's were inactive as antivirals and largely inactive against tumor cells in culture. In contrast to the 5'-monophosphates, the 5-R-cdUMP's failed to inhibit thymidylate synthetase from L1210 cells.

Animals↗
PubMed1986

Structure-activity relationship of novel oligopeptide antiviral and antitumor agents related to netropsin and distamycin.

A group of oligopeptides have been synthesized that are structurally related to the natural antiviral antitumor agents netropsin and distamycin. Cytostatic activity against both human and murine tumor cell lines as well as their in vitro activity against a range of viruses is reported. The biological activity of these agents is discussed both in terms of their structural differences and, in particular, in relation to their observed base- and sequence-dependent minor-groove binding to duplex oligonucleotides.

Animals↗