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 1,063 records · Page 59Linked to original sources

PubMedDate not supplied

Synthesis and conformation analysis of 3-substituted derivatives of 1H,3H-pyrido[2,3-d] pyrimidin-4-one of expected depressive nervous system. Part III.

Four series of new 1-aryl (heteroaryl) piperazinylacetyl derivatives of 1H,3H-pyrido[2,3-d] pyrimidin-4-one VIIa-o were synthesised. Substrates for the synthesis of VIa-d were obtained from the respective 3H-pyrido[2.3-d]pyrimidines IVa-d in the reaction with NaBH4. Compounds VIa-d were prepared by chloroacetylation. The obtained 1-chloroacetyl derivatives in the reaction with respective aryl (heteroaryl) piperazine formed 1-aminoacetyl derivatives of 2-phenyl-1 H.3H-pyrido[2.3-d]pyrimidin-4-one compounds VII1a-n. The structure ol compounds was analysed by 1H, 13C NMR spectroscopy.

Central Nervous System Depressants↗

PubMedDate not supplied

Studies of pyrimidine metabolism during chick development: two enzymes involved in UMP breakdown.

The pattern of uridylate phosphatase and uridine phosphorylase has been studied in the liver, brain, heart and thigh muscles of the chick during development. The study of enzymes involved in pyrimidine metabolism confirms that differences in utilisation of the metabolic pathways exist during ontogenesis. In the liver, starting from the 12th day, an active metabolic pathway, leading to UMP via cytosine should be added to the catabolic ones. In the brain, the second period of embryogenesis should be characterized by a lower utilisation of the catabolic pathways and by an increase of the anabolic ones. In the heart, pyrimidine metabolism during development regards especially UMP. In skeletal muscle, pyrimidine metabolism shows low activity.

5'-Nucleotidase↗

PubMed1988

Interferon effects upon the adenocarcinoma 38 and HL-60 cell lines: antiproliferative responses and synergistic interactions with halogenated pyrimidine antimetabolites.

In order to gain insight into the mechanisms affecting combination treatment of tumor cells with interferon and halogenated pyrimidine antimetabolites, in vitro studies of murine colon adenocarcinoma 38 and HL-60 cell lines were undertaken. Interferons exhibited modest antiproliferative effects against these lines with DNA synthesis inhibited greater than RNA greater than protein synthesis, as studied by 3H-precursor incorporation. The adenocarcinoma cell line was considerably more sensitive to recombinant gamma-than to purified alpha/beta-interferon, while HL-60 was slightly more sensitive, in short term studies, to antiproliferative effects of recombinant alpha- than to gamma-interferon. Interferon treatment was further associated with suppression of a hyperdiploid component of the adenocarcinoma cell line, as detected by flow cytometry. Combination treatment of the adenocarcinoma cell line with interferon and halogenated pyrimidines, under 4-day continuous exposure conditions, revealed significant synergy for growth inhibition with gamma- much greater than alpha/beta-interferon and with 5-fluorodeoxyuridine greater than 5-fluorouracil much greater than 5-fluorouridine. Thus, synergy was much greater with the more antiproliferative interferon and with the antimetabolite derivative most likely to lead to thymidylate synthetase inhibition rather than RNA incorporation. Sequential 2-day + 2-day treatment revealed greater synergy when interferon preceded 5-fluorouracil or 5-fluorodeoxyuridine rather than the reverse protocol. The synergy of gamma-interferon and 5-fluorodeoxyuridine could be blocked by thymidine, which bypasses inhibition of thymidylate synthetase. HL-60 also exhibited thymidine antagonized synergistic growth-inhibitory effects of interferon and 5-fluorouracil. Analysis of this interaction by [3H]thymidine incorporation, which can reflect thymidylate synthase inhibition, revealed exaggerated responses of interferon-treated cells to either 5-fluorouracil or 5-fluorodeoxyuridine. These results indicate that interferon-halogenated pyrimidine antimetabolite synergistic interactions may be common to several cell types. Evidence is further presented for a mechanism of synergy entailing enhanced thymidylate synthetase inhibition by the antimetabolite of interferon-treated cells.

Adenocarcinoma↗

PubMed1989

Pyrimidine 5'-nucleosidase in Neisseria meningitidis. An enzyme specific for uridine 5'-monophosphate.

A previously unknown pyrimidine 5'-nucleosidase (pyrimidine 5'-nucleotide phosphoribohydrolase) specific for uridine 5'-monophosphate (5'-UMP) was present in crude extract from Neisseria meningitidis. Of seven strains, six were found to degrade the N-glycosidic linkage of 5'-UMP. One strain showed negligible activity. The substrate was quantitatively converted to uracil and ribose 5'-phosphate (R5P). Cytidine 5'-monophosphate (5'-CMP) or the 2-deoxy 5'-monophosphates of the pyrimidine nucleosides (5'-dUMP, 5'-dCMP, 5'-dTMP) were found not to be degraded. Neither was uridine 3'-monophosphate (3'-UMP) degraded by extracts from the three strains selected for this test.

N-Glycosyl Hydrolases↗

PubMed1987

Substrate specificity and pH sensitivity of deoxyribonucleotidase and pyrimidine nucleotidase activities in human hemolysates.

Residual 5'-nucleotidase activities in hemolysates from nine subjects with severe hereditary deficiency of pyrimidine nucleotidase (PyrNase) were compared to those in normal and reticulocyte-rich controls. Dephosphorylation rates of 12 potential ribo- and deoxyribomononucleotide substrates were measured as a function of pH. Data confirmed the existence of at least two isozymes of 5'-nucleotidase, PyrNase, and 2'-deoxy-5'-ribonucleotide phosphohydrolase (dNase) distinguishable by differences in maximal velocities, substrate preferences and restrictions, and pH optima. PyrNase was confirmed to be active principally with pyrimidine substrates (UMP = dCMP greater than CMP much greater than dTMP greater than dUMP) at a pH optimum of 7.5 +/- 0.1. dNase activity occurred with both purine and pyrimidine substrates and was maximal with deoxy analogs (dIMP much greater than dUMP greater than dGMP greater than dTMP = dAMP much greater than dCMP) at a pH optimum of 6.2, but slight cross-reactivity occurred with some nondeoxy substrates (IMP greater than GMP greater than UMP = XMP greater than CMP). PyrNase and dNase may be complementary systems that serve physiologically to clear the cytosol of RNA and DNA degradation products during maturation of erythroid elements by conversion of nucleotide monophosphates to diffusible nucleosides.

5'-Nucleotidase↗

PubMed1986

Effects on immune reactions of non-steroidal anti-inflammatory drugs and of two new pyrido-pyrimidine derivatives (CHINOIN 127 and CHINOIN 105).

The effect of three non-steroidal anti-inflammatory agents (NSAIs) and of two new pyrido-pyrimidine derivatives, CHINOIN 127 (1-6-dimethyl-4-oxo-1,6,7,8,9)a-hexahydro-4H-pyrido (1,2-2)pyrimidine-3-carboxamide) and CHINOIN 105 (1-6-dimethyl-4-oxo-1,6,7,8-tetrahydro-4H pyrido (1,2-a) pyrimidine-3-carboxamide) was compared in immune tests using human cells in vitro including T and B lymphocyte proliferation induced with mitogens, spontaneous motility of polymorphonuclear leukocytes, lymphokine (LIF) production, antibody-dependent cell-mediated cytotoxicity (ADCC) and natural killer cell (NK) activity. Indomethacin (INDO) at therapeutic concentrations enhanced the proliferation of lymphocytes stimulated by both Con A and PWM. Acetylsalicylic acid (ASA) increased proliferation of lymphocytes stimulated by Con A and at high concentration inhibited DNA synthesis induced by PWM. Phenylbutazone (PhB) increased DNA synthesis induced by PWM but not by Con A. CHINOIN 127 and CHINOIN 105 inhibited the proliferation of T lymphocytes but failed to influence DNA synthesis of B cells. Indomethacin, ASA and PhB inhibited the spontaneous motility (migration) of polymorphonuclear leukocytes. LIF production of lymphocytes was inhibited by INDO, ASA, PhB, CHINOIN 127 and CHINOIN 105. Phenylbutazone and ASA inhibit ADCC and NK. INDO, Chinoin 127 and Chinoin 105 failed to influence the effector cells of ADC and NK cytotoxicity.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1987

Degradation of the pyrimidine bases uracil and thymine by Escherichia coli B.

Degradation of the pyrimidine bases uracil and thymine by Escherichia coli B was investigated. The known products of the reductive pathway of pyrimidine base catabolism were tested to determine if they could support the growth of E. coli B cells as sole sources of nitrogen or carbon. As might be expected if the reductive pathway was present, it was found that dihydrouracil, N-carbamoyl-beta-alanine, beta-alanine, dihydrothymine and beta-aminoisobutyric acid could sustain the growth of the bacterial cells as sole nitrogen sources by at least a fourteen-fold greater level than that observed if they were included as sole carbon sources. The existence of the reductive pathway of pyrimidine base degradation was confirmed in this micro-organism, since dihydrouracil, N-carbamoyl-beta-alanine and beta-alanine were detected following thin-layer chromatographic separation of the catabolic products of uracil and dihydrouracil.

Biotransformation↗

PubMed1976

[Isolation of mitochondrial DNA, purified of nuclear DNA, from animal tissues (degree of methylation and level of pyrimidine nucleotide clustering--criteria of purity)].

A method of preparation of mitochondria free of nuclear DNA and its fragments by treatment of mitochondria with DEAE-cellulose has been developed. This method is based on binding nuclear nucleic acids and nucleoproteins to DEAE-cellulose particles in the media used for isolation of mitochondria. Treatment with DEAE-cellulose under the conditions described does not induce any visible degradation of mitochondria and mitochondrial DNA. The mitochondrial DNA preparations obtained from beef and rat liver are represented with closed circular molecules of contour length about 5.5 mu. The 5-methylcytosine content in beef and rat mitochondrial DNA (3.03 and 2.0 mole %, respectively) is twice as much as in corresponding nuclear DNA. Besides, mitochondrial DNA strongly differs from nuclear ones by a lower degree of pyrimidine clustering: the amount of mono- and dipyrimidine fragments (about 32 mole %) in mitochondrial DNA is 1.5 times as large and the content of long pyrimidine clusters (hexa- and others) is 2--4 times as low as those in nuclear DNA. The methylation level and the pyrimidine clustering degree may be used as criteria for the purity of mitochondrial DNA from nuclear DNA.

Animals↗

PubMed1984

Pyrimidine de novo synthesis during the life cycle of the intraerythrocytic stage of Plasmodium falciparum.

The 6 enzymes involved in de novo synthesis of pyrimidines were measured in Plasmodium falciparum isolated by saponin lysis from RBC's nonsynchronized and synchronized in vitro cultures. The total activities were found to be dependent on the stage of the P. falciparum cycle. In parasites isolated from synchronized cultures, the highest activities for all enzymes were found at about 27 hr after synchronization in the late trophozoite stage, or just before schizont formation. Merozoites and ring forms contained little de novo activity. The first enzyme of the pathway, carbamyl phosphate synthetase (CPS-II) preferentially utilized glutamine. Ammonia was a poor substrate. CPS-II was unstable in the absence of the cryoprotectants, dimethylsulfoxide and glycerol. The apparent Km for MgATP--was 3.8 +/- 0.7 mM and the enzyme in all morphological forms of P. falciparum (ring, mature trophozoites and schizonts) was inhibited by UTP. The activity of the fourth enzyme of the pathway, dihydroorotate dehydrogenase, appeared to be linked to the cell's respiratory chain; inhibitors of mammalian electron transport such as cyanide, amytal, antimycin A, thenoyltrifluoroacetone and ubiquinone analogs also inhibited the P. falciparum enzyme. The demonstration of the variation of activity of the pyrimidine enzymes correlates with the increased synthesis of nucleic acids in the late trophozoite stage. These observations provide a basis for the testing of the effectiveness of pyrimidine analogs as potential antimetabolites against various forms of the parasite.

Adenosine Triphosphate↗

PubMed1982

A homogeneous cyclic CMP phosphodiesterase hydrolyzes both pyrimidine and purine cyclic 2':3'- and 3':5'-nucleotides.

A homogeneous preparation of cyclic CMP phosphodiesterase (Helfman, D. M., Shoji, M., and Kuo, J. F. (1981) J. Biol. Chem. 256, 6327-6334) was found to catalyze the hydrolysis of both pyrimidine and purine cyclic 2':3'- and 3':5'-nucleotides. Hydrolysis of cyclic 2':3'-nucleotides resulted in the formation of both 2'- and 3'-nucleotides, although relative amounts of the products were variable. Hydrolysis of cyclic 2':3'-CMP or cyclic 2':3'-UMP yielded predominantly 3'-nucleotides. In contrast, hydrolysis of cyclic 2':3'-AMP produced equal amounts of 2'- and 3'-nucleotides, while the major product formed from cyclic 2':3'-GMP was 2'-nucleotide. When conventional pyrimidine and purine cyclic 3:5'-nucleotides were used as substrates, the enzyme hydrolyzed specifically the 3'-bond to yield only 5'-nucleotides. The relative rate of hydrolysis of cyclic 2':3'-nucleotides was cyclic CMP greater than cyclic UMP greater than cyclic GMP greater than or equal to cyclic AMP, respectively, whereas that for cyclic 3':5'-nucleotides was cyclic CMP greater than cyclic UMP greater than or equal to cyclic AMP greater than cyclic GMP, respectively. Furthermore, kinetic analysis suggested a single species of catalytic site on the enzyme may be involved in the hydrolysis of both pyrimidine and purine cyclic 2':3'- and 3':5'-nucleotides. These findings indicate that the present enzyme is the first multifunctional phosphodiesterase reported to date that is capable of hydrolyzing such a diversity of cyclic nucleotides.

2',3'-Cyclic Nucleotide 3'-Phosphodiesterase↗

PubMed1981

New pharmacologically active 2-phenylpyrazolo [1,5-a]pyrimidines.

2-Phenylpryrazolo [1,5-a]pyrimidine (I) 4,7-dihydro-2-phenylpyrazolo [1,5-a]pyrimidin-7-one (II) and 4,5-dihydro-2-phenylpyrazolo [1,5-a]pyrimidin-5-one (III) are prepared. Because of the interesting antipyretic, hypothermizing and anti-inflammatory properties of some of their derivatives, the above mentioned compounds are used as reference compounds in a Q.S.A.R. study still in progress. Methylation of (II) and (III) with (CH3)2SO4 and CH2N2 gives methylderivatives whose structure is determined by spectroscopic means.

Animals↗

PubMed1995

New 2,3-substituted 4,7-dihydro-6-(1'H-pyrazol-3'-yl)pyrazolo[1,5-a] pyrimidin-7-ones and related compounds: synthesis and benzodiazepine receptor binding study.

The reaction between two series of 7-dimethylaminovinyl pyrazolo[1,5-a]pyrimidines 4(a-r) 7a, 7d, 7f, 7(h-j) and hydrazine in acetic acid is investigated. The structure of 4,7-dihydro-6-(1'H-pyrazol-3'-yl)pyrazolo[1,5-a]pyrimidin-7- ones 5(a-r) and 7-methyl-6-(1'H-pyrazol-3'-yl)pyrazolo[1,5-a]pyrimidines 8a, 8d, 8f, 8(h-j) are attributed to the isolated products and the pathway of this reaction is suggested. The in vitro benzodiazepine receptor (BzR) affinity of the title compounds are determined by testing their ability to displace 3H-flunitrazepam from its specific binding in bovine brain membranes. The IC50 and GABA (gamma-aminobutyric acid) ratio values give valuable indications about affinity and behavioural profile of these new BzR ligands. Included in this investigation are indicated several structure-affinity relationships of the title compounds.

Animals↗

PubMed1976

[Frequency distribution of pyrimidine isopliths in the DNA of actinophage F448 and Actinomyces coelicolor 66].

Base composition distribution of pyrimidine isopliths with general formula PyrnPn+1 in DNA of Actinomyces coelicolor 66 Kras. and in DNK of its actinophage F448 were investigater. These DNAs differ both pyrimidine isoplith distribution and in composition. The quality of shorter pyrimidine tracts in Actinomyces coelicolor DNA is higher compared with that in actinophage F448 DNA. The possibility of exogenic origin of actinophage F448 is discussed.

Bacteriophages↗

PubMed1977

Purine and pyrimidine metabolism: pathways, pitfalls and perturbations.

The conceptual framework which underlies many studies of purine and pyrimidine metabolism in intact cells has been critically evaluated. The model that is implicit in many such studies is the single, partially purified enzyme. This paper gives examples both of instances in which the extrapolation of results of enzymes studies to intact cells has been successful and of instances in which enzymes behave differently in the intact cell than in cell extracts. Pitfalls in the extrapolation of results of enzyme studies to intact cells concern (a) metabolic pathways, (b) intracellular enzyme activities, (c) enzyme regulation, and (d) intracellular metabolite concentrations. Examples are also given of situations in which perturbations in one aspect of purine or pyrimidine metabolism lead to changes in other aspects, often distant in the network of reactions.

Adenine Phosphoribosyltransferase↗

PubMed1982

Pyrimidine ribonucleoside phosphorylase activity vs 5- and/or 6-substituted uracil and uridine analogues, including conformational aspects.

The pyrimidine ribonucleoside phosphorylase from Salmonella typhimurium phosphorylyses 6-methyluridine, a uridine analogue sterically constrained to the syn conformation about the glycosylic bond, as effectively as uridine itself. In conjunction with the observation that 3-methyluridine is a very poor substrate compared to 5-methyluridine and 5,6-dimethyluridine, it follows that the phosphorolysis reaction involves the initial conversion of uridine, and other 5-substituted uridines (including 5-fluorouridine), to the syn conformation during interaction with the enzyme. Furthermore, and consistent with the foregoing, the enzyme recognizes as substrates, to varying degrees, the N(3)-ribosides of xanthine and uric acid, and will also catalyze the formation of these ribosides from the corresponding purines, which may be considered formally as 5,6-disubstituted uracils. Similar observations are reported for the synthetic 5,6-trimethyleneuridine. The enzyme does not, however, recognize 6-methyluracil and 5,6-tetramethyleneuridine in the reverse, synthetic, reaction. The conformational aspects of these reactions are discussed. Since it was previously shown that 6-methyluridine is an equally effective substrate for the pyrimidine phosphorylase of primary rabbit kidney cells, at least some of these conformational requirements apply to the enzyme from mammalian sources, and are consequently of relevance in the design of chemotherapeutic agents, for which some examples are cited.

Molecular Conformation↗

PubMed1975

Radiation-sensitive pyrimidine auxotrophs of Ustilago maydis. II. A study of repair mechanisms and UV recovery in pyr I.

Two mutants at the pyr I locus have been used to study the radiation sensitivity of pyrimidine auxotrophs of U. maydis. The mutant pry I-I has a reduced level of thymidine nucleotides, and this is a likely basis of the sensitivity. This strain is able to excise pyrimidine dimers from its DNA and is cross-sensitive to gamma-rays and nitrosoguanidine (NG) as well as to UV. A diploid heteroallelic at the pyr I locus was UV-sensitive but not deficient in UV-induced mitotic recombination. The results suggest that the UV sensitivity may be due to the failure of a repair DNA polymerase to fill post-excision single-strand gaps in the DNA. The mutant pyr I-I exhibits the property of UV recovery, and this is shown to be dependent on the presence of dimers in the DNA. A mechanism for UV recovery is proposed in which a repair system, possibly involving recombination, is induced by the UV irradiation.

Basidiomycota↗

PubMed1993

Pathways of pyrimidine nucleotide biosynthesis in gravid Angiostrongylus cantonensis.

The incorporation of radioactive precursors into pyrimidine nucleotides via de novo and salvage pathways was measured in gravid Angiostrongylus cantonensis by HPLC and thin-layer chromatography. 14C-labelled orotate, uridine, uracil and deoxyuridine were traced to UMP, UDP, UTP, UDP-glucose, dTMP, CMP, CDP and CTP. 3H-labelled cytidine was also incorporated into both uracil and cytosine nucleotides in a ratio of 2:1. Cytosine was a major end-product for all the precursors. Cytosine nucleotides were probably formed from UTP by the action of CTP synthetase whose activity in crude cell-free extract was 31.5 +/- 4.9 pmol min-1 (mg protein)-1. It was dependent on glutamine, ATP and GTP and was inhibited by CTP. The total amount of pyrimidine nucleotides formed from uridine was 3 times of that from uracil. The presence of uracil in the metabolism of uridine indicates that UMP is formed by uracil phosphoribosyltransferase as well as by uridine kinase. UMP is a key intermediate for cytidylate and thymidylate biosynthesis in the gravid worms.

Angiostrongylus cantonensis↗

PubMed1986

Bifilar enzyme-sensitive sites in ultraviolet-irradiated DNA are indicative of closely opposed cyclobutyl pyrimidine dimers.

Incubation of UV-irradiated DNA with pyrimidine dimer-DNA glycosylase in cell-free lysates prepared from Micrococcus luteus results in the appearance of double-strand breaks. It has previously been assumed that such double-strand breaks result from cleavage at closely opposed dimers. We have used hybrid molecules of bacteriophage T7 DNA comprised of two unirradiated strands, two UV-irradiated strands, or one unirradiated and one UV-irradiated strand to test this hypothesis. Bifilar cleavage was observed only with molecules consisting of two irradiated strands and no bifilar cleavage was observed after the monomerization of pyrimidine dimers by enzymatic photoreactivation. Our results indicate that at least 80% of the double-strand breaks result from cleavage at closely opposed dimers and that the induction of dimers in one strand does not influence the induction of dimers at closely opposed positions in the complementary strand of a DNA double helix.

Carbon Radioisotopes↗