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Biomedical subjects

T J Bardos

Publications and source records attributed to T J Bardos.

At least 37 records · Page 2Linked to original sources
PubMed1981

Synthesis and antiviral activity of 1-(2-deoxy-beta-D-ribofuranosyl)-5-(methylmercapto)-2-pyrimidinone.

1-(2-Deoxy-beta-D-ribofuranosyl)-5-(methylmercapto)-2-pyrimidinone (1b) was synthesized via modification of the silyl method. 1b inhibits the Herpes simplex virus type 1 (98%) and type 2 (97%) at a concentration which is nontoxic to human HeLa cells. The compound shows 50 times greater binding affinity (lower Ki) to the virus-specific thymidine kinase than to the thymidine kinase of uninfected HeLa cells.

Antiviral Agents↗
PubMed1981

Synthesis of 5'-thymidinyl bis(1-aziridinyl)phosphinates as antineoplastic agents.

Reaction of 3'-acetylthymidine with phosphorus oxychloride in trimethyl phosphate yielded the phosphorodichloridate 5, which was subsequently reacted with aziridine, or 2,2-dimethylaziridine to give compounds 6 and 7, respectively. The 2,2-dimethylaziridine derivative 7 was considerably more active than 6 against leukemia L1210 and P-388 in mice but less active than the previously synthesized, simpler phosphinate derivatives 2 and 3. It appears that the thymidine moiety did not enable these compounds to use the nucleoside transport mechanism of the cells and also failed to increase the selectivity of the 2,2-dimethylaziridine analogues by interference with their binding to cholinesterase. Compound 7 strongly inhibited horse serum cholinesterase, while 6 was inactive.

Animals↗
PubMed1980

Enzymatic synthesis of polyuridylic acid containing modified bases.

5'Mercaptouridine-5'-diphosphate (hs5UDP) has been synthesized and investigated as a substrate of the polynucleotide phosphorylase of Micrococcus luteus. While hs5UDP is not utilized alone, it can be copolymerized with UDP; however, unusually for this enzyme, the ratio of 5'mercaptouridylate vs. uridylate residues in the polynucleotide product (MPU) is always lower than the ratio of hs5UDP v. UDP in the substrate mixture. Furthermore, hs5UDP decreases the rate of the enzymic polymerization reaction. The MPU product forms two-stranded and three-stranded complexes with poly(A). The circular dichroic spectra of these complexes are similar to those formed between poly(U) and poly(A), but their melting profiles indicate somewhat lower stability. The physicochemical and biochemical properties of the enzymic product are qualitatively similar to those of MPU prepared by chemical modification; both are potent inhibitors of a DNA-dependent RNA polymerase.

Circular Dichroism↗
PubMed1980

Synthesis of some new S-alkylated derivatives of 5-mercapto-2'-deoxyuridine as potential antiviral agents.

A series of S-alkylated derivatives of 5-mercapto-2'-deoxyuridine have been prepared by alkylation of the preformed nucleoside. Two of these compounds, the S-propargyl and S-allyl derivatives, have shown significant antiviral activity against Herpes simplex type 1 in HeLa TK- cells but appear to be less effective in this assay system than some previously reported 5-substituted 2'-deoxyuridines.

Alkylation↗
PubMed1980

Radiation sensitizing agents in clinical radiation and chemotherapy.

Patients with bronchogenic carcinoma or with advanced pediatric solid tumours were treated with various radiation therapy schedules alone or with a new alkylating carbamate: AB 132. Drug therapy appeared to potentiate radiation therapy results without significant toxicity except for certain neurologic symptoms (myasthenia, nightmares, disturbances of taste and smell). The latter appeared to be related to acetylcholinesterase and pseudocholinesterase inhibition.

Aziridines↗
PubMed1979

Synthesis of 5-selenium-substituted uracil derivatives. Inhibition of thymidylate synthetase by 5-hydroseleno-2'-deoxyuridylate.

5-Selenium-substituted derivatives (diselenides) or uracil, 2'-deoxyuridine, and 2'-deoxyuridylic acid were synthesized via the addition of methyl hypobromite to the 5,6 double bond, followed by reaction of the adducts with sodium diselenide. The physical and chemical properties of these compounds (including their facile reduction by dithiothreitol and rapid reoxidation) were similar to those of the corresponding 5-sulfur analogues. 5-Hydroseleno-2'-deoxyuridylic acid was as potent as 5-mercapto-2'-deoxyuridylate in inhibiting thymidylate synthetase from L. casei (ki approximately 6 X 10(-8) M) but the nucleoside III was considerably less active than 5-mercapto-2'-deoxyuridine in the inhibition of growth of the leukemia L1210 cell in culture.

Animals↗
PubMed1979

Effects of partially thiolated polycytidylic acid on the clonogenicity of murine leukemic stem cells.

The effect of partially thiolated polycytidylic acid (MPC) on the colony-forming ability of the progenitor cells (CFUC) of RF/Un leukemic mice was investigated using the plasma clot method in order to study the mode of action of the modified polynucleotide. The results showed that MPC inhibited the CFUC in a dose-dependent and time-dependent manner. Once a maximum level of inhibition of CFUC (approximately 40%) was observed, no further inhibition occurred whether the concentration of MPC was increased or whether the duration of incubation was lengthened. High-specific-activity [3H]thymidine, an S-phase-specific agent, showed a similar inhibition profile on the CFUC as did MPC. When MPC and high-specific-activity [3H]thymidine were incubated together with the bone marrow cells, there was no additive or synergistic inhibitory effect on the CFUC. Thus, it appears that MPC is an S-phase-specific agent. When injected i.v. into the mice, MPC decreased the number of CFUC of both the bone marrow and the spleen significantly.

Animals↗
PubMed1977

Synthesis and inhibition analysis of 2(4)-imino-4(2)-amino-2,4-dideoxyriboflavin, a dual antagonist of riboflavin and folinic acid.

The synthesis of the 2,4-diamino analogue of riboflavin is described. Inhibition analysis in a microbial assay system indicated that this compound has a weak antifolate activity that could be overcome with a minimal amount of folinic acid, but at higher concentrations both folinic acid and riboflavin were required for the reversal of its inhibitory effect.

Depression, Chemical↗
PubMed1976

Oligonucleotides containing modified bases. I. Inhibition of DNA and RNA polymerases by partially thiolated oligocytidylic acids.

A series of oligomers of cytidylic acid were prepared and partially (6-9% of the bases) thiolated in the 5 positions. The modified oligomers showed increasing inhibition with increasing chain length of both the DNA polymerase-alpha from regenerating rat liver and the DNA-dependent RNA polymerase of E. coli, but the minimum chain length for observable inhibitory activity was 5 nucleotide units for the DNA polymerase-alpha and 16 units for the RNA polymerase.

Animals↗
PubMed1976

Differential effects of 5-methylmercapto-2'-deoxyuridine on the replication of herpes simplex virus type 1 in two cell systems.

5-Methylmercapto-2'-deoxyuridine (MeMUdR), a structural analogue of thymidine (TdR), inhibits herpes simplex virus type 1 production in mouse L (Lb) cells at concentrations that are not inhibitory to viral growth in monkey kidney (CV-1) cells. It is moderately toxic to Lb cells but not to CV-1 cells at a concentration that causes 95% inhibition of viral replication in Lb cells. MeMUdR is incorporated into cellular and viral deoxyribonucleic acid (DNA) in both systems, but to a significantly higher level (compared with thymidine) in Lb cells. These results indicate that MeMUdR is a substrate for enzymes leading to DNA synthesis and suggest that the biological function of herpes simplex virus type 1 DNA is impaired only when the incorporation of MeMUdR into the DNA reaches a relatively high level.

Animals↗
PubMed1976

Action of partially thiolated polynucleotides on the DNA polymerase alpha from regenerating rat liver.

The effects of partially thiolated polynucleotides on the DNA polymerase alpha from regenerating rat liver were investigated. The enzyme was isolated from the nuclear fraction essentially according to the method of Baril et al.; it was characterized as the alpha polymerase on the basis of its response to synthetic templates and its inhibition with N-ethylmaleimide. Although polycytidylic acid had no effect on the DNA polymerase alpha either as a template or as an inhibitor, partially thiolated polycytidylic acid (MPC) was found to be a potent inhibitor, its activity being directly related to its extent of thiolation (percentage of 5-mercaptocytidylate units in the polymer). In comparison, the DNA polymerase beta which was purified from normal rat liver nuclear fraction, was much less sensitive to inhibition by MPC. Analysis of the inhibition of the alpha polymerase by the method of Lineweaver and Burk showed that the inhibitory action of MPC was competitively reversible with the DNA template, but the binding of the 7.2%-thiolated MPC to the enzyme was much stronger than that of the template (Ki/Km less than 0.03). Polyuridylic acid as such showed some inhibitory activity which increased on partial thiolation, but the 8.4%-thiolated polyuridylic acid was less active than the 7.2% MPC. When MPC was annealed with polyinosinic acid, it lost 80% of its inhibitory activity in the double-stranded configuration. However, 1 to 2%-thiolated DNA isolates were significantly more potent inhibitors than were comparable (1.2%-thiolated) MPC and showed competitive reversibility with the unmodified (but "activated") DNA template. These results indicate that the inhibitory activities of partially thiolated polynucleotides depend not only on the percentage of 5-mercapto groups but also on the configuration, base composition, and other specific structural properties.

Animals↗
PubMed1976

Uptake of partially thiolated DNA by ascites tumor cells.

The uptake and intracellular localization by Ehrlich ascites cells of partially [35S]thiolated homologous DNA ("antitemplate") were studied in comparison with that of the corresponding unmodified [3H]DNA, at 37 degrees and 0 degrees, under standardized conditions. For the unmodified DNA, washing the cells after incubation with 0.08 M iodoacetate (in 0.15 M NaCl) alone gave high but reproducible uptake values (23%); washing with 1 M NaCl reduced the cell-associated DNA to 12% (less than 1% at 0 degrees). It appears that 1 M NaCl is able to remove DNA reversibly bound to the cells, similarly to DNase treatment. Approximately 5% of the input [3H]DNA was taken up into the cell nuclei. Diethylaminoethyl dextran (1:1, by weight) greatly enhanced the cellular uptake of [3H]DNA. In the case of [35S]thiolated DNA, the rate as well as the extent of uptake was significantly higher (33%). Washing the cells with 1 M NaCl or treatment with DNase caused relatively small decrease in the total cell-associated [35S]thiolated DNA, the bulk of which (22% of input) was recovered in the isolated nuclei. Stimulation by diethylaminoethyl dextran of the uptake of [35S]thiolated DNA could not be established because of the insolubility of the 1:1 complex in 1 M NaCl. Excess calcium ions during incubation dramatically increased the uptake of the thiolated DNA at 37 degrees (but not at 0 degrees) by the cells (to 90 to 100%) and into the nuclear fraction (to 70% of the total [35S]DNA input). The calcium salt procedure appears to be applicable to the in vivo testing of thiolated DNA's as potential chemotherapeutic agents.

Animals↗
PubMed1976

Effects of 5-mercapto-2'-deoxyuridine on the incorporation of nucleosides into RNA and DNA in a primary lymphocyte culture system.

The effects of 5-mercapto-2'-deoxyuridine (MUdr) on DNA synthesis in a primary murine spleen lymphocyte culture system stimulated by phytohemagglutinin (PHA) were studied. Inhibition of thymidine incorporation into acid insoluble nucleic acid material was 50% at 0.5 mM MUdR concentration, while inhibition of deoxyuridine incorporation into acid-insoluble nucleic acids was 50% at 0.01 mM MUdR. Time course studies, at 0.5 and 0.05 mM MUdR, showed that the magnitude of inhibition of incorporation for thymidine and deoxyuridine, respectively, increased from a time point after PHA stimulation when increased synthesis of thymidine kinase and thymidylate synthetase had leveled off. At 1 mM MUdR, total cellular DNA in cultures was decreased 43% at 42 hr after PHA stimulation. Neither the total number of cells nor the percentage of PHA-transformed cells was decreased in comparison to that of controls. MUdR therefore blocks the increase in DNA content of lymphocytes that is initiated during the S phase of the cell cycle. Millimolar levels of MUdR inhibited incorporation or uridine, adenosine, and cytidine into acid-insoluble material in pha-stimulated primary murine lymphocyte cultures. Total cellular RNA synthesis was inhibited at these levels of MUdR, with no differential effects on 4, 18, or 28 S RNA species observed. Uptake of these nucleosides into the total cellular acid-soluble material was not blocked. Uptake of different labeled nucleosides into cellular, acid-soluble pools occurs at different rates. Thus, choice of a suitable minimum pulse time to achieve saturation for different labeled nucleosides must relate to this consideration. Thymidine kinase from whole-cell sonic extracts of PHA-stimulated lymphocytes was inhibited 65% by 1 mM MUdR at 24 and 48 hr after stimulation. Uridine kinase extracted from the PHA-stimulated cells was also significantly inhibited by 1mM MUdR at 24 hr (56%). Exogenous guanosine incorporation into lympohcyte acid-insoluble material is increased by MUdR. This increased utilization of exogenous nuceloside is apparently the result of MUdR inhibition of conversion of adenosine to guanine nucleotides within the lymphocytes and a consequent diminution of the total intracellular guanine nucleotide pool size. The active inhibitory compound is the deoxyribonucleoside or deoxyribonucleotide. Comparison with the riboside analog 5-mercaptouridine showed that MUdR was a more efficient inhibitor of nucleoside incorporation.

Animals↗