PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “PYRIMIDINES”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,009 records · Page 56Linked to original sources
PubMed1993

Synthesis and positive inotropic activity of several 5-aminopyrido[2,3-d]pyrimidines. Part 5: Compounds with positive inotropic activity.

Starting from 6-amino-1,3-dimethyluracil two approaches were developed for the preparation of 5-amino-pyrido[2,3-d]pyrimidine derivatives as potential cardiotonic agents. 1. Gould-Jacobs reaction followed by chlorination of the intermediate 5-hydroxypyrido-[2,3-d]pyrimidine using DMF/POCl3. 2. Cyclization of C-acetylated as well as C-cyano acetylated 6-amino-1,3-dimethyluracil by an application of the Vilsmeier reaction yielding 5-chloropyrido[2,3-d]pyrimidines. Subsequent nucleophilic substitution reactions formed the target compounds which were examined for positive inotropic activity on isolated left atria and papillary muscles from guinea-pig hearts. Structure-activity relationships indicated that the effect depended on the 4-aminopyridine-3-carboxylic acid derivative structure.

Action Potentials↗
PubMed1993

Application of simple chromatographic methods for the diagnosis of defects in pyrimidine degradation.

Recent findings suggest that inborn errors of pyrimidine catabolism are less rare than generally assumed. We propose a complete set of diagnostic methods for these disorders, suitable for the clinical chemistry laboratory, and present relevant reference data. Applications of thin-layer chromatography, high-performance liquid chromatography, and conventional cation-exchange amino acid analysis lead to detection of various defects in pyrimidine degradation, including the recently described deficiencies of dihydropyrimidine dehydrogenase and dihydropyrimidinase. We also illustrate the potential of the methods to analyze for the catabolites expected to be increased in the urine of patients with ureidopropionase deficiency. Possible pitfalls in the diagnosis and ways to prevent misdiagnosis are demonstrated. The methods offer possibilities for clinical chemistry laboratories to extend their diagnostic capacity to the new area of pyrimidine degradation defects.

Animals↗
PubMed1977

Induction and persistence of pyrimidine dimers in the epidermal DNA of two strains of hairless mice.

The ultraviolet-light induction of DNA damage has been measured in the epidermis of hairless mice with the use of damage-specific endonucleases from Micrococcus luteus. The rates of induction of endonuclease-sensitive sites in HRS/J/Anl and Skh:hairless-1 mice were 6.1 +/- 0.5 X 10(-11) and 6.5 +/- 0.8 X 10(-11)/dalton/J/sq m from a FS40 fluorescent sun lamp (280 to 400 nm), respectively. Enzymatic photoreactivation with yeast photoreactivating enzyme showed that approximately 80% of the endonuclease-sensitive sites were cycloburyl pyrimidine dimers. In both strains of mice the pyrimidine dimers remained in high-molecular-weight DNA for 24 hr after irradiation. These data show that mouse epithelial cells in vivo have little or no capacity for the excision repair of pyrimidine dimers.

Animals↗
PubMed1977

[Some peculiarities of pyrimidine isoplyth methylation of newly synthesized DNA from human blood lymphocytes in normal conditions and chronic lymphoycytic leukemia].

Methylation of pyrimidine isoplythes of newly synthesized DNA from activated human blood lymphocytes was studied under normal conditions and in chronic lymphocytic leukemia. The analysis of distribution of labelled 5-methylcytosine in DNA pyrimidine oligonucleotides, differing in their lengths, showed a considerable increase in the methylation of pyrimidine oligonucleotide fragments of DNA from lymphocytic leukemia lymphocytes as compared to normal. The greatest differences were observed in methylation with respect to longer fragments, e.g. under chronic lymphocytic leukemia the level of methylation of the cytosine residues of DNA in isoplythes I and II, as well as in the fraction of isoplyth III and in longer fragments exceeded that of the normal DNA isoplythes, 3.7-, 2.1- and 8.3-fold respectively.

Cytosine↗
PubMed1996

Transport of adenosine by recombinant purine- and pyrimidine-selective sodium/nucleoside cotransporters from rat jejunum expressed in Xenopus laevis oocytes.

Two major Na+-dependent nucleoside transporter subtypes implicated in adenosine transport in mammalian cells are distinguished functionally on the basis of substrate specificity: one is selective for pyrimidine nucleosides but also binds adenosine, and the other has selectivity for purine nucleosides but also binds uridine. Transportability of adenosine by the purine-selective system has been established by measurements of [3H]adenosine fluxes, whereas the conclusion that adenosine is permeant of the pyrimidine-selective system is based on inhibition assays. We investigated adenosine transport mediated by a recombinant pyrimidine-selective rat jejunal/kidney Na+/nucleoside cotransporter (rCNT1) expressed in Xenopus laevis oocytes and compared it with that mediated by a recombinant purine-selective rat jejunal/liver Na+/nucleoside cotransporter (rCNT2). Adenosine fluxes mediated by rCNT1 were 1 order of magnitude lower than those mediated by rCNT2. In kinetic studies, rCNT1 transported adenosine with an apparent Km value for influx (26 microM) similar to that for uridine but with a very much lower Vmax value, and the Vmax/Km ratios were 0.003 and 0.57 for adenosine and uridine, respectively. Recombinant rCNT1 mediated efflux of [3H]uridine from preloaded oocytes, demonstrating a capacity for bidirectional transport of nucleoside permeants. Uridine efflux was stimulated by extracellular uridine and inhibited by extracellular adenosine, suggesting that the rate of conversion of rCNT1 from its outward-facing conformation to its inward-facing conformation was increased when the transporter was complexed with uridine and decreased when it was complexed with adenosine. Thus, although rCNT1 binds adenosine and uridine with similar affinities, it kinetically favors transport of uridine.

Adenosine↗
PubMed1998

[Pyrimidine derivatives increase antibiotic therapy efficacy after ionizing irradiation].

Pyrimidine derivatives increased the antibiotic therapy efficacy in albino rats irradiated with RUM-7 apparatus for close-focus roentgenotherapy. 2-Methyl-4-amino-6-oxypyrimidine was twice as efficient as oxymethyluracil and 6 times as efficient as methyluracil in the stimulation of the skin reparative regeneration. When the total irradiation was performed with LUCH-1 apparatus in a dose of 6 Gy the pyrimidine derivatives also increased the antibiotic therapy efficacy. After the prophylactic use of the pyrimidine derivatives for 7 days prior to the total irradiation their therapeutic effect increased, the level of the exudative component lowered, the tissue epithelization increased, the terms of the wound healing decreased and the animal lifespan increased.

Administration, Topical↗
PubMed1984

Metabolism of pyrimidine bases and nucleosides in the coryneform bacteria Brevibacterium ammoniagenes and Micrococcus luteus.

The metabolism of exogenous pyrimidine bases and nucleosides was investigated in Brevibacterium ammoniagenes and Micrococcus luteus with fluorinated analogs and radioactive precursors. Salvage of thymine and thymidine was found in M. luteus, but not in B. ammoniagenes. Exogenous uracil or uracil nucleosides, but not cytosine or cytosine nucleosides, were nucleic acid precursors for both bacteria. By examining the possible nucleoside-metabolizing enzymes, it can be suggested that the pyrimidine salvage pathways in the coryneform bacteria are different from those of members of the family Enterobacteriaceae.

Brevibacterium↗
PubMed1986

Biosynthesis of pyrimidine nucleotides in human leukemic cells.

The biosynthetic pathways of pyrimidine nucleotides were studied in cells obtained from 10 patients with acute leukemia (AL), 3 with chronic myelocytic leukemia in blastic crisis (CML-crisis) and 4 with chronic myelocytic leukemia (CML) and from 8 controls. In the de novo pathway, synthesis of intermediates was analyzed with NaH[14C]O3 as a tracer. In the salvage pathway, the formation of nucleotides and free bases was studied with [3H]nucleosides (uridine, cytidine, thymidine, deoxyuridine, and deoxycytidine) tracers. Radioactivities of nucleotides were significantly lower in AL and CML-crisis cells than in CML and control cells in both pathways. These results suggest that the proliferative rate of cells was lower in the former cases than in the latter. Biosynthetic activities of nucleotides in the salvage pathway were about 100-300 times higher than those in the de novo pathway. It was calculated however, that as much as 70% of the amount of nucleic acids necessary for AL cells can be supplied by de novo biosynthesis, while in normal bone marrow cells the figure was about 30%. The greater part of pyrimidine biosynthesis can be carried out through the de novo pathway. In particular, AL cells with a longer generation time seemed to depend more on de novo biosynthesis than do normal bone marrow cells. This finding could be important in connection with the design of antileukemic agents.

Adult↗
PubMed2005

Isomerization/Recyclization of some 5-Ethoxycarbonyl-pyrimidines.

This communication reports on the investigation of a new recyclization conversion of a pyrimidine ring, which can be referred to as C-C recyclization. In this reaction the nucleophile cleaves the pyrimidine ring at the N(3)-C(4) bond, and following rotation around the single C(5)-C(6) bond the new cyclization takes place. This type of recyclization has general applicability, and takes place upon alkali treatment of substituted 4-methyl-5-ethoxycarbonyl- and 4-amino-5-ethoxycarbonyl-pyrimidines (1) which are transformed respectively to 4-hydroxy-5-acetyl- and 4-hydroxy-5-carbamoylpyrimidines (2). The obtained pyrimidyl-ketones can be readily converted to their hydrazones 7-12.

Journal Article↗
PubMed1990

Pyrimidine ribonucleoside catabolism in Pseudomonas fluorescens biotype A.

The pyrimidine ribonucleosides uridine or cytidine were shown to serve as a source of nitrogen or carbon for the growth of Pseudomonas fluorescens strain A126. After incubation of either pyrimidine ribonucleoside with extracts of this strain, the resultant catabolic products were detected by thin-layer chromatography. It was found that pyrimidine ribonucleoside catabolism in this pseudomonad involved the enzymes nucleoside hydrolase and cytosine deaminase. The specific activities of both these enzymes could be influenced by the nitrogen or carbon source present in the medium.

Carbon↗
PubMed1990

Conversion of 5-aminoimidazole ribotide to the pyrimidine of thiamin in enterobacteria: study of the pathway with specifically labeled samples of riboside.

Samples of 5-amino-1-(beta-D-ribofuranosyl)imidazole labeled with 13C at position C-1 or C-2 of the ribose part or with 15N at position N-3 or amino of the imidazole part were prepared by chemical synthesis. The incorporation of label from these samples into the pyrimidine of thiamin biosynthesized by a mutant strain of Salmonella typhimurium was studied by GC-MS. The results show clearly that in enterobacteria the methyl carbon atom and the N-1 nitrogen atom of one molecule of thiamin pyrimidine derive from the same molecule of 5-aminoimidazole ribotide. More specifically, the methyl carbon atom comes from the carbon C-2' of the ribose part and the nitrogen N-1 from nitrogen N-3 of the imidazole; furthermore, the amino nitrogen of the aminoimidazole becomes the amino nitrogen of the pyrimidine.

Carbon Isotopes↗
PubMed1990

The dependence of halogenated pyrimidine incorporation and radiosensitization on the duration of drug exposure.

The influence of the duration of exposure to the halogenated pyrimidines iododeoxyuridine (IdUrd) and bromodeoxyuridine (BrdUrd) on incorporation into DNA and the resulting radiosensitization was studied in cultured human colon cancer cells. Cells were incubated with either 10 microM BrdUrd or IdUrd for periods up to 7 days. They were also assessed for up to 4 days after removal of drug from the medium. Replacement of thymidine by fraudulent bases was measured using a sensitive gas chromatographic, mass spectrometric (GC/MS) assay. Incorporation of BrdUrd and IdUrd plateaued at 35% and 30%, respectively, after 4 days of exposure. Prolonging the time of exposure to 7 days increased cytotoxicity without affecting either incorporation or radiosensitization. Incorporation remained constant for 1-2 days after removal of drug from the medium. Radiosensitization was linearly related to incorporation throughout the range of conditions assessed. These data suggest that it may be possible to develop a predictive assay for radiosensitization based on measurements of halogenated pyrimidine incorporation in a tumor biopsy specimen. They also suggest that a clinical approach based on repeated short exposures to halogenated pyrimidines may present certain advantages over the current practice of prolonged continuous exposure. A Phase I/II trial using IdUrd and external beam irradiation for the treatment of patients with poor prognosis soft tissue sarcomas has been initiated based on this concept.

Bromodeoxyuridine↗
PubMed2004

Novel imidazo[1,2-c]pyrimidine base-modified nucleosides: synthesis and antiviral evaluation.

The preparation of a series of novel 6-(beta-D-ribofuranosyl)-2-alkyl/aryl-6H-imidazo[1,2-c]pyrimidin-5-one nucleosides and the 2-nitrile nucleosides, 6-(beta-D-ribofuranosyl)-5-oxo-5,6-dihydro-imidazo[1,2-c]pyrimidine-2-carbonitrile and 2R and 2S isomers of 6-(beta-D-ribofuranosyl)-5-oxo-2,3,5,6-tetrahydro-imidazo[1,2-c]pyrimidine-2-carbonitrile, is described using two synthetic approaches. The nucleoside mimetics described were evaluated against a wide range of viral types and strains in cell culture. With the exception of one nucleoside, which displayed anti-CMV activity at toxic concentrations, none of the compounds showed antiviral activity most likely due to a lack of substrate recognition by viral and/or cellular nucleoside kinases.

Animals↗
PubMed1996

Anti-recombinogenic and convertible co-mutagenic effects of (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and other 5-substituted pyrimidine nucleoside analogs in S. cerevisiae MP1.

In experiments using yeast, without addition of an external metabolic activation system, (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) was co-mutagenic and showed an insignificant anti-recombinogenic effect in combination with triethylene melamine (TEM). In the presence of activating S9-mix, the anti-recombinogenicity and co-mutagenicity could clearly be seen. At higher concentrations the co-mutagenic effect was converted into anti-mutagenicity. The other three 5-substituted pyrimidine nucleoside analogs were tested only in the presence of activating S9-mix and showed similar effects. As TEM is a direct alkylating agent that is inactivated by liver microsomes, the higher activity in presence of S9-mix can be interpreted as resulting from metabolic activation of the 5-substituted pyrimidine nucleoside analogs. In previous experiments using yeast bacteria, Drosophila or mice, tumor promoters were co-recombinogenic/anti-mutagenic, and co-carcinogens were co-mutagenic/anti-recombinogenic. Thus, there is not only an operational difference between tumor promoters and co-carcinogens but a real difference in respect to their genetic effectiveness. As up to now only co-carcinogens have shown co-mutagenic and anti-recombinogenic effects, it is perhaps possible that, within a certain concentration range, 5-substituted pyrimidine nucleoside analogs may have co-carcinogenic activity in carcinogenicity tests. At higher concentrations the co-carcinogenic effect may be converted into an anti-carcinogenic one.

Animals↗
PubMed1995

Mechanism-based inactivation of tRNA-guanine transglycosylase from Escherichia coli by 2-amino-5-(fluoromethyl)pyrrolo[2,3-d]pyrimidin-4 (3H)-one.

In Escherichia coli, tRNA-guanine transglycosylase (TGT) catalyzes the incorporation of the queuine precursor preQ1 [2-amino-5-(aminomethyl)pyrrolo[2,3-d]pyrimidin-4(3H)-one] into tRNA. This precursor is further elaborated to queuine by two subsequent enzymic reactions [Slany, R. K., & Kersten, H. (1994) Biochimie 76, 1178-1182]. Our previous studies [Hoops, G. C., Townsend, L. B., & Garcia, G. A., (1995) Biochemistry (in press)] on a series of synthetic 5- and 6-substituted 2-aminopyrrolo[2,3-d]pyrimidin-4(3H) -ones have revealed that the E. coli TGT tolerates a wide diversity of substituents (isosteric, or nearly so, to the aminomethyl group of preQ1) at the 5 position. We report here that 2-amino-5-(fluoromethyl)pyrrolo[2,3-d]pyrimidin-4 (3H)-one (FMPP) inactivates TGT in a time- and concentration-dependent manner with k(inact) = 0.074 min-1 and KI = 136 microM. A competitive inhibitor (7-methyl-preQ1), with respect to preQ1, of TGT [Hoops, G.C., Townsend, L.B., & Garcia, G.A. (1995) Biochemistry (in press)] protects the enzyme from inactivation by FMPP. FMPP also acts as a competitive inhibitor (KI = 114 microM) of TGT under initial velocity conditions. The rate of fluoride release from FMPP is slightly faster (0.064 min-1) than the k(inact) (0.053 min-1) at 300 microM FMPP, consistent with fluoride release preceding inactivation. FMPP appears to partition between "normal" turnover (kcat = 0.461 min-1 and Km = 152 microM), inactivation, and an alternative processing to an unidentified, fluoride-released product.(ABSTRACT TRUNCATED AT 250 WORDS)

Enzyme Inhibitors↗
PubMed1997

Effects of chain length modification and bis(ethyl) substitution of spermine analogs on purine-purine-pyrimidine triplex DNA stabilization, aggregation, and conformational transitions.

The natural polyamines--putrescine, spermidine, and spermine--are known to stabilize pyrimidine-purine-pyrimidine and purine-purine-pyrimidine triplex DNA formation. We studied the ability of two tetramine and two pentamine analogs of spermine and their bis(ethyl) derivatives to stabilize triplex DNA formation between 5'-TG3TG4TG4TG3T-3' and its target duplex probe, consisting of the oligonucleotides 5'-TCGAAG3AG4AG4AG3A-3' and 5'-TCGATC3TC4TC4TC3T-3'. We used electrophoretic mobility shift assay (EMSA), melting temperature (Tm) measurements, and circular dichroism (CD) spectroscopy to evaluate the effects of these novel polyamine analogs on triplex DNA stability, dissociation constants, aggregation, and conformation. In general, pentamines were more efficacious than tetramines in stabilizing triplex DNA, although most of the polyamines with pendant free amino groups caused DNA aggregation below 50% conversion to triplex DNA. Ethyl substitution of these pendant amino groups lowered their efficacy approximately 2-fold in stabilizing triplex DNA; however, this effect was more than compensated for by the lack of DNA aggregation in the presence of bis(ethyl)polyamines. A concentration-dependent increase in the Tm of triplex DNA was observed in the presence of polyamines. CD spectral measurements showed distinct differences in the conformation of triplex DNA stabilized in the presence of polyamines compared to the CD spectra of the oligonucleotides alone. Temperature-dependent CD spectra of triplex DNA showed monophasic melting in the absence and presence of polyamines, suggesting duplex/triplex --> single-stranded DNA transition. These results indicate that structural modifications of polyamines is an effective strategy to develop triplex DNA-stabilizing ligands, with potential applications in antigene therapeutics.

Circular Dichroism↗
PubMed2000

Effect of C9-methyl substitution and C8-C9 conformational restriction on antifolate and antitumor activity of classical 5-substituted 2,4-diaminofuro[2,3-d]pyrimidines.

N-[4-[1-methyl-2-(2,4-diaminofuro[2, 3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid (5) and its C8-C9 conformationally restricted E- and Z-isomers (6 and 7) were designed and synthesized in order to investigate the effect of incorporating a methyl group at the C9 position and of conformational restriction at the C8-C9 bridge of N-[4-[2-(2,4-diaminofuro[2, 3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid (1) with respect to dihydrofolate reductase (DHFR) inhibitory activity as well as antitumor activity. The compounds were synthesized by a Wittig reaction of 2,4-diamino-5-(chloromethyl)furo[2,3-d]pyrimidine with ethyl 4-acetylbenzoate followed by catalytic reduction, hydrolysis, and standard peptide coupling with diethyl L-glutamate. The biological results indicated that the addition of a 9-methyl group to the C8-C9 bridge, as in 5, increased recombinant human (rh) DHFR inhibitory potency (IC(50) = 0.42 microM) as well as the potency against the growth inhibition of tumor cells in culture (CCRF-CEM EC(50) = 29 nM, A253 EC(50) = 28.5 nM, and FaDu EC(50) = 17.5 nM) compared with the 9-desmethyl analogue 1. However, the conformationally restricted 4:1 Z/E mixture of 7 and 6 was less potent than 5 in both assays, and the pure E-isomer 6 was essentially inactive. These three classical analogues were also evaluated as inhibitors of Lactobacillus casei, Escherichia coli, and rat and rh thymidylate synthase (TS) and were found to be weak inhibitors. All three analogues 5-7 were good substrates for human folylpolyglutamate synthetase (FPGS). These data suggested that FPGS is relatively tolerant to different conformations in the bridge region. Further evaluation of the cytotoxicity of 5 and 7 in methotrexate (MTX)-resistant CCRF-CEM cell sublines suggested that polyglutamylation was crucial for their mechanism of action. Metabolite protection studies of 5 implicated DHFR as the primary intracellular target. Compound 5 showed GI(50) values in 10(-9)-10(-7) M range against more than 30 tumor cell lines in culture.

Animals↗