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PubMed2006

[Retarded excision of pyrimidine dimers in human unstimulated lymphocytes].

Using immuno-labelling of cyclobutane pyrimidine dimers (CPDs) in nuclei of peripheral lymphocytes after their UVC-irradiation and cultivation, we have found that within the first four hours of cultivation the CPD-specific fluorescent signal from cell nuclei increased. Earlier, a similar increase in binding of antibody specific for pyrimidine (6-4) pyrimidone photoproducts to undenatured DNA isolated from UV-irradiated Chinese hamster ovary cells was reported (Mitchell et al., 1986). Our experiments showed that nucleotide excision repair enzyme might induce such of DNA modification in lymphocyte nuclei that increased specific antibody binding to DNA fragments with lesions. We suggest that enzymatic formation of open structures in DNA predominated qualitatively over dual-incision and excision of these fragments, and resulted in the enhanced exposure of the pyrimidine dimers in nuclei to specific antibodies. The results evidence that nucleotid excision repair in unstimualted human lymphocytes being deficient in dual incision and removal of UV-induced DNA lesions appear to be capable of performing chromatin relaxation and pre-incision uncoiling of DNA fragments with lesions.

Cell Nucleus↗
PubMedDate not supplied

Synthesis and biological activity of pyrimido[2,1-b][1,3]thiazine, [1,3]thiazino[3,2-a]purine and [1,2,3]triazolo[4,5-d][1,3]thiazino[3,2-a]pyrimidine derivatives and thiazole analogues.

Some series of thiazolo[3,2-a]pyrimidine, pyrimido[2,1-b] [1,3]thiazine, thiazolo[3,2-a]purine, [1,3]thiazino[3,2-a]purine, thiazolo[3,2-a][1,2,3]triazolo[4,5-d]pyrimidine and [1,2,3]triazolo[4,5-d][1,3]thiazino[3,2-a]pyrimidine derivatives, variously functionalized, were prepared. The compounds were tested for antimicrobial and antimycotic activity on a number of strains, namely: E. coli, Proteus vulgaris, P. mirabilis, Pseudomonas aeruginosa, Salmonella sp., Staphylococcus aureus, S. faecalis, Bacillus subtilis, Sarcina lutea, Candida albicans, C. tropicalis, Aspergillus sp., and for antiviral activity on Herpes simplex virus Type 1, Vesicular stomatitis virus and Coxsackievirus B5. The compounds proved to be devoid of activity against viruses and gram-negative bacteria, while some of them exhibited modest activity against gram-positive bacterial strains.

Anti-Bacterial Agents↗
PubMed1976

Inhibition of de novo pyrimidine nucleotide and DNA synthesis and growth of cultured Novikoff rat hepatoma cells and other cell lines by pyrazofurin (NSC 143095).

Pyrazofurin (PYF), a C-riboside, inhibited the replication of cultured Novikoff rat hepatoma cells, HeLa cells, and mouse L-cells at concentrations as low as 0.1 to 10 muM, but Novikoff cells were more sensitive than the cells of the other two cell lines. Inhibition of cell replication was completely prevented by the presence of 0.1 to 1 mM uridine in the medium, and partly by the presence of other pyrimidine, but not purine nucleosides. A 2- to 4-hr treatment of the cells with 10 muM PYF resulted in a 2-fold increase in the rate of incorporation of uridine into the acid-soluble pool and nucleic acids, while the rate of incorporation of adenosine into RNA was reduced about 85%. The incorporation of adenosine and deoxyuridine into DNA were reduced about 85 and 50%, respectively. The results are consistent with the view that PYF inhibits the de novo synthesis of pyrimidine nucleosides. The inhibition of cell replication seems to be due mainly to an inhibition of DNA rather than RNA synthesis, resulting from a rapid depletion of the pyrimidine deoxynucleotide pool, since addition of thymidine and deoxycytidine reversed the inhibition of DNA synthesis and cell replication by PYF. PYF must enter the cells to exert its toxicity since the toxicity of PYF was reduced 70 to 80% by the presence of 8 muM Persantin, a potent inhibitor of the facilitated and simple diffusion of various substrates, in the medium. If PYF is incorporated via normal nucleoside salvage pathways, its affinity for the nucleoside transport system(s) and kinases, must be low since, even at a concentration of 1 mM, it had only a slight effect on the initial rates of incorporation of various nucleosides into the nucleotide pool.

Adenosine↗
PubMedDate not supplied

[Pyrimidine derivatives: their psychotropic properties and the molecular mechanisms of their central action].

The data on the neuro- and psychotropic effects of exo- and endogenous derivatives of pyrimidine are systematized. Uridine is characterized as an endogenous anxiolytic and antidepressant and thimidine as uridine antagonist. The given properties are probably determined by the binding of pyrimidine nucleosides to GABA, benzodiazepine and imipramine receptors as well as by their influence on the neuromediator systems. The involvement of the system of endogenous pyrimidines in the development of psychoneurological disturbances in man is shown.

Animals↗
PubMed1979

Measurement of pyrimidine dimers in spheroplasts of Bacillus subtilis.

A method is described for making spheroplasts of Bacillus subtilis which are permeable to exogenous enzymes. Conditions are described for measuring small numbers of pyrimidine dimers in the DNA of UV-irradiated cells by use of a partially purified Micrococcus luteus extract containing an enzyme specific for pyrimidine dimers. The system will detect as few as 10-12 pyrimidine dimers per genome.

Bacillus subtilis↗
PubMedDate not supplied

[Distribution of pyrimidine blocks in the DNA of Brevibacterium linens, Arthrobacter globiformis, Nocardia corallina and Nocardia rubra].

The nucleotide composition and the frequency of pyrimidine blocks were studied in DNA of the following bacteria: Brevibacterium linens (Weignamm, 1910) Breed, 1953; Arthrobacter globiformis (Conn, 1928) Conn et Dimmick, 1947; Nocardia corallina (Bergey et al., 1923) Waksman et Henrici, 1948; Nocardia rubra (Krassilnikov, 1949) Waksman et Henrici, 1948. These organisms are classed by some microbiologists as mycobacteria (the Mycobacteriaceae family) while other authors regard them as representatives of three families belonging to two orders. About 60 percent of all pyrimidines in DNA of these bacteria are found in the sequences pur-pyr-pur and pur-pyr-pyr-pur, the number of dipyrimidines being higher than the amount of monopyrimidine nucleotides. The content of dipyrimidine nucleotides in DNA of Nocardia corallina and Nocardia rubra is higher (16.8 mole %) than the content of dipyrimidine blocks in DNA of Brevibacterium linens and Arthrobacter globiformis, in which the quantity of dipyrimidines is almost the same (13.9 and 14.4 mole %). A new characteristic, the selected mean value, is suggested to evaluate differences in the distribution of pyrimidines in DNA.

Arthrobacter↗
PubMed1989

Pyrimidine biosynthesis in Mycobacterium leprae and other intracellular mycobacteria.

All the enzymes which could be detected in mycobacteria that are unique to the de novo pathway of pyrimidine biosynthesis were shown (in cell extracts) in M. leprae. Activity of the first enzyme in the pathway, aspartate transcarbamylase was shown in M. microti and M. avium grown in vivo and in liquid Dubos medium. This suggested that the very low activity of pyrimidine biosynthesis de novo in intact M. microti and M. avium grown in vivo, and the failure to detect any activity in M. leprae, is a result of feedback inhibition of the metabolic pathway for pyrimidine biosynthesis as opposed to any lack of metabolic capability.

Aspartate Carbamoyltransferase↗
PubMed1989

Effects of pyrimidine nucleoside phosphorylase inhibitors on hepatic fluoropyrimidine elimination in the rat.

The breakdown of 5-fluoro-2'-deoxyuridine (FdUrd) to 5-fluorouracil (FUra) is catalyzed by the pyrimidine nucleoside phosphorylases, uridine phosphorylase and thymidine phosphorylase. The effects of nucleoside phosphorylase inhibitors on FdUrd and FUra elimination by the isolated perfused rat liver were investigated. The inhibitor was injected into the perfusion reservoir 5 min before FdUrd or FUra, and serial perfusion fluid samples were collected for fluoropyrimidine analysis. The disappearance of each fluoropyrimidine followed Michaelis-Menten kinetics, as shown previously. 6-Benzyl-2-thiouracil, a thymidine phosphorylase-selective inhibitor, and 1-(2'-deoxy-beta-D-glucopyranosyl)thymine, a uridine phosphorylase-selective inhibitor, each decreased the rate of FdUrd disappearance (apparent Ki, 1.4-1.6 and 3.8 mM, respectively) but had no direct effect on FUra disappearance. However, 6-benzyl-2-thiouracil decreased the peak concentration of FUra derived from administered FdUrd and increased the t 1/2 of disappearance of derived FUra due to its delayed formation. 2,6-Dihydroxypyridine, a uridine phosphorylase-selective inhibitor, decreased the rate of FdUrd disappearance (apparent Ki, 12.4-16.2 microM) and directly inhibited FUra elimination (apparent Ki, 4.3-5.3 microM). 2,4-Dihydroxypyridine, which does not inhibit pyrimidine nucleoside phosphorylases, directly inhibited FUra elimination (apparent Ki, 77 microM) and also decreased the rate of FdUrd disappearance, possibly due to product (FUra) inhibition. It was concluded that the hepatic elimination of FdUrd is slowed by pyrimidine nucleoside phosphorylase inhibitors and that some of these drugs block FUra, as well as FdUrd, elimination.

Animals↗
PubMed1989

Synthesis of certain heteroaryl-fused pyrimidines and pyridines and selena- and thia-diazoles with naphthyl substituent as potential antifungal agents.

A convenient route is reported for the synthesis of 1,2,3-selenadiazole, 1,2,3-thiadiazole, 1,2,4-triazolo[4,3-a]pyrimidine, tetrazolo[4,5-a]pyrimidine, benzimidazolo[1,2-a]pyrimidine and pyrazolo[3,4-b]pyridine derivatives in which the naphthyl nucleus is incorporated. The preliminary results of antifungal testing are reported.

Antifungal Agents↗
PubMed1989

Dual effects of pyrazofurin and 3-deazauridine upon pyrimidine and purine biosynthesis in mouse L1210 leukemia.

Pyrazofurin (NSC 143095) as the monophosphate derivative is a potent inhibitor of orotidine 5'-monophosphate (OMP) decarboxylase of the pyrimidine pathway and has been proposed to inhibit 5-aminoimidazole-4-carboxamide ribotide (AICAR) transformylase (EC 2.1.2.3) of the purine pathway (J. F. Worzalla, and M. J. Sweeney, Pyrazofurin inhibition of purine biosynthesis via 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranosyl 5'-monophosphate formyltransferase. Cancer Res., 40: 1482-1485, 1980). Measurement of levels of pyrimidine and purine intermediates in cultured mouse L1210 leukemia cells has shown that 25 microM pyrazofurin induces an 8-fold accumulation of OMP and large accumulations of intermediates proximal to the blockade with abrupt decreases in uridine and cytidine nucleotides. Considerable increases in the cellular concentrations of N-succino-AICAR (SAICAR), AICAR, 5-formamidoimidazole-4-carboxamide ribotide (FAICAR), IMP, XMP, and GMP at later times indicate that AICAR transformylase is not significantly inhibited in cultured cells; rather the purine pathway and the GMP branch are stimulated. However, addition of 25 microM 3-deazauridine (NSC 126849) to leukemia cells did result in inhibition of AICAR transformylase: AICAR and SAICAR accumulated, IMP disappeared and there was a large accumulation of guanosine nucleotides. Blockade of pyrimidine biosynthesis by derivatives of pyrazofurin or 3-deazauridine spares 5-phosphoribosyl-1-pyrophosphate and L-glutamine, elevated concentrations of which may stimulate initial reactions of purine biosynthesis and the reaction XMP----GMP.

3-Deazauridine↗
PubMed1988

Sonolysis, radiolysis, and hydrogen peroxide photolysis of pyrimidine derivatives in aqueous solutions: a spin-trapping study.

The sonolysis of aqueous solutions of various dihydropyrimidines and substituted pyrimidines was investigated by ESR and spin trapping with the nonvolatile, water soluble spin trap, 3,5-dibromonitrosobenzene sulfonate (DBNBS) and its deuterated analog to examine the possibility of detecting new radicals specifically generated in the high temperature zones produced by collapsing cavitation bubbles. Similar ESR spectra were obtained from sonolysis of argon-saturated aqueous solutions, from uv photolysis of aqueous solutions containing H2O2, and from gamma radiolysis of nitrous oxide saturated solutions, although sonolysis of aqueous solutions leads to the formation of pyrimidine radicals by H atom as well as OH radical addition to the 5,6 double bond of pyrimidines. No evidence for specific new radicals formed in the high temperature regions induced by cavitation could be found. For the reactions of dihydropyrimidines with hydroxyl radicals additional spin adducts could be detected and identified with the spin trap DBNBS compared to 2-methyl-2-nitrosopropane which was used in previous studies; however, for alkylpyrimidines fewer spin adducts were observed. The use of the deuterated analog of DBNBS is helpful for unambiguous radical structure assignment.

Benzenesulfonates↗
PubMed1988

Sunscreen protection against UV-induced pyrimidine dimers in DNA of human skin in situ.

We have determined the ability of a chemical sunscreen with a sun protection factor (SPF) of 15 to protect human skin from ultraviolet (UV) radiation-induced DNA damage. The DNA damage was susceptible to cleavage by Micrococcus luteus UV endonuclease, which recognizes pyrimidine dimers in DNA. An alkaline agarose gel electrophoresis method was used to quantify the number of pyrimidine dimers in nonradioactive DNA from skin biopsies of 5 individuals irradiated with UV from a solar simulator. After exposure to an equivalent dose of UV, the number of pyrimidine dimers was 0.8 per 10(7) bases in sunscreen-treated skin as compared with 32 dimers per 10(7) bases in untreated skin. This assay provides a means of determining the efficacy of sunscreens in protecting skin from UV-induced DNA damage.

DNA↗
PubMed1988

[The anti-H1-histaminic and antimuscarinic effect of 2- and 4-[benzyl-(2-dimethylaminoethyl)amino]pyrimidine compounds].

This paper reports the synthesis of 2- and 4- [benzyl-(2-dimethylaminoethyl)amino]pyrimidine compounds and the evaluation of their inhibitory properties against histamine (H1), acetylcholine and barium chloride, on guinea pig isolated ileum. 4-[p.Methoxybenzyl-(2-dimethylaminoethyl)amino]-2-methoxy-pyrimidine (VIII) is shown to possess H1 receptor antagonist activity, with a potency similar to that observed for Tonzylamine. By contrast, a specific, although weak, antimuscarinic effect is displayed by 4-[benzyl-(2-dimethylaminoethyl)amino]-2-methoxy-5-methylthio-pyrimidine (XII).

Acetylcholine↗
PubMed1987

Synthesis of some 7-phenylpyrrolo[1,2-a]pyrimidine derivatives. III.

2-Amino-4-phenylpyrrolyl-3-carbonitrile (I) was reacted with ethyl formylacetate sodium salt affording 1,4-dihydro-4-oxo-7-phenylpyrolo[1,2-a]pyrimidin-8-carbonitrile (II), which was alkylated with EtI to give (III), which in turn was hydrolyzed to (IV). Treatment of both (III) and (IV) with 99% H3PO4 at approximately 200 degrees gave 1,4-dihydro-1-ethyl-7-phenylpyrrolo-[1,2-a]pyrimidin-4-one (V) whose structure was ascertained by an unequivocal synthesis starting from (I) and diethyl ethoxymethylenmalonate. Compound (V) was prepared in order to test its pharmacological properties in comparison with 4,7-dihydro-4-ethyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-one, which showed an antiinflammatory activity comparable to that of phenylbutazone and indomethacine, and which was found devoid of ulcerogenic properties.

Animals↗
PubMedDate not supplied

Synthesis and antitumor properties of pyrazolo [3,4-D] pyrimidine derivatives.

Several new 5-substituted 1-phenylpyrazole [3,4-d] pyrimidine derivatives were synthesized and tested for antitumor activity. Compound 17, which has 3,4-dichlorophenyl moiety at N5 of the pyrazole pyrimidine ring, shows a strong activity against L-1210 leukemia (152%). On the other hand, compounds 15, 17 and 21 were the most active against sarcoma Sa-180. It was observed that many derivatives of pyrazole [3,4-d] pyrimidine possess different biological, especially antitumor properties [1-6, 9, 10].

Animals↗
PubMedDate not supplied

[Use of a pyrimidine-dependent mutant for effective labeling of the DNA OF Aspergillus nidulans].

Incorporation of the radioactive label from pyrimidines into RNA and DNA of an Aspergillus nidulans pyrimidine-dependent mutant was studied. The label from [14C2]uridine was incorporated at the highest rate into both fractions of nucleic acids from A. nidulans of the wild type and pyr-mutant. The content of the label in the DNA of the pyr-mutant was several times higher than that in the wild type DNA. Therefore, pyr-mutants can be used in order to study molecular-genetic processes in the cells of A. nidulans. The label from [3H5]deoxyuridine, [14C2]thymine, [14C2]thymidine, [14C2]cytosine and I114C2]uracil was incorporated into the pyr-mutant RNA and DNA at a much lower rate than into the wild type RNA and DNA. Apparently, these pyrimidines cannot maintain the growth of the pyr-mutant. Incorporation of the label from [14C2]uracil into the pyr-mutant DNA increased if growth of the mycelium was stimulated by low concentrations of unlabeled uridine.

Aspergillus nidulans↗
PubMedDate not supplied

[Metabolic pathways of exogenous pyrimidines in Aspergillus nidulans].

Studies on the susceptibility of the wild-type strain of Aspergillus nidulans to 6-azauracil suggest that it synthesizes pyrimidines using a by-pass pathway which is induced with 6-azauracil. The effect of a series of pyrimidines on the toxic action of 5-fluorouracil, 5-fluorouidine and 5-fluorodeoxyuridine has been investigated. As the result of these studies, a scheme is proposed for the metabolism of some pyrimidine bases and nucleosides in Aso. nidulans.

Aspergillus nidulans↗