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PubMed1994

Evidence from CD spectra that d(purine).r(pyrimidine) and r(purine).d(pyrimidine) hybrids are in different structural classes.

CD spectra and difference CD spectra of four d(oligopurine).r(oligopyrimidine) and four r(oligopurine).d(oligopyrimidine) hybrid duplexes containing mixed A.T(U) and G.C base pairs were compared with the spectra of four DNA.DNA and four RNA.RNA oligomer duplexes of similar repeating sequences. The 16 duplexes were formed by mixing oligomers that were 24 nucleotides long. The buffer was 0.05 M Na+ (phosphate), pH 7.0. DNA.DNA and RNA.RNA oligomer duplexes were used as reference B-form and A-form structures. We found that the CD spectra of d(purine).r(pyrimidine) and r(purine).d(pyrimidine) hybrid duplexes were different from the CD spectra of either DNA.DNA or RNA.RNA duplexes. The data suggested that these hybrids have intermediate structures between A-form RNA and B-form DNA structures. The CD spectra of d(purine).r(pyrimidine) and r(purine).d(pyrimidine) hybrid duplexes were different from each other, but the hybrids in each class had consistent CD spectra as indicated by nearest-neighbor comparisons. Thus, it appeared that the two types of hybrids belonged to different structural classes. The negative 210 nm band found in difference CD spectra was correlated with the presence of an r(purine) strand in the hybrid duplexes. The melting temperatures (Tm values) of these hybrids were compared with the Tm values of the DNA.DNA and RNA.RNA duplexes. The order of the thermal stability was: RNA.RNA duplex > r(purine).d(pyrimidine) hybrid > DNA.DNA duplex > d(purine).r(pyrimidine) hybrid, when comparing analogous sequences.

Base Composition↗
PubMed1988

Combination effects of cis-dichlorodiammineplatinum with selected metahalones, pyrimidine sulfoxides and pyrimidine sulfones on human NHIK 3025 cells in vitro.

Synergistic cell inactivating effects were displayed when human NHIK 3025 cells cultivated in vitro were treated with cis-dichlorodiammineplatinum(II) (cis-DDP) in simultaneous combination with selected metahalones, pyrimidine sulfoxides and sulfones. Cell inactivation was measured as the percentage of single cells surviving and able to give rise to macroscopic colonies following drug treatment. Selection of compounds was made according to the presence and position of certain structural groups. For 5-halo-pyrimidin-2-ones (the metahalones), a propargyl substituent attached to the pyrimidine ring at the 1-position resulted in compounds causing potentiation of cis-DDP-induced cell inactivation. An iodo or trifluoromethyl substituent at the 5-position led to a reduction in cis-DDP + metahalone synergism respective to a 5-chloro substituent. Cell survival following 1 h treatment with the metahalones alone was always near 100%. The cell inactivating effect of pyrimidine sulfoxides and sulfones alone and in simultaneous combination with cis-DDP was also investigated. Treatment of human cells with pyrimidine sulfoxides and sulfones alone resulted in reduced cell survival relative to the metahalones. When tested in combination with cis-DDP, pyrimidine sulfoxides and sulfones containing a propargyl moiety bound at the sulfur atom were found to potentiate the cell inactivating effect of cis-DDP. Other substituents induced only minor effects.

Cell Survival↗
PubMed1990

Thiazolo[4,5-d]pyrimidine nucleosides. The synthesis of certain 3-beta-D-ribofuranosylthiazolo[4,5-d]pyrimidines as potential immunotherapeutic agents.

Novel analogues of the naturally occurring purine nucleosides were synthesized in the thiazolo[4,5-d]pyrimidine ring system to determine the immunomodulatory effects of insertion of a sulfur atom in place of nitrogen at position 7 of the purine ring. In particular, 5-amino-3-beta-D-ribofuranosylthiazolo[4,5-d]pyrimidine-2,7(3H,6H) -dione (7, guanosine analogue), 3-beta-D-ribofuranosylthiazolo[4,5-d]pyrimidine-2,5,7(3H,4H,6H) trione (8, xanthosine analogue), 3-beta-D-ribofuranosylthiazolo[4,5-d]pyrimidine-2,7(3H,6H)-dione (10, inosine analogue), and 7-amino-3-beta-D-ribofuranosylthiazolo[4,5-d]pyrimidin-2(3H)-one (32, adenosine analogue) were prepared, as well as the 8-mercaptoguanosine (14) and 6-mercaptoguanosine (17) analogues. Single-crystal X-ray studies confirmed the structural assignment of 17 and 32 as having the beta-configuration with the site of glycosylation at N3. The nucleosides were evaluated for their ability to potentiate various murine immune functions in direct comparison to the known active agents 8-bromoguanosine (1), 8-mercaptoguanosine (2), and 7-methyl-8-oxoguanosine (3). Two of the guanosine analogues, 7 and 14, were found to exhibit significant immunoactivity relative to the positive control compounds (1-3), while the adenosine, inosine, xanthosine, and 6-mercaptoguanosine analogues were devoid of activity. Compound 7 exhibited greater immunoactivity than any of the other guanosine analogues and derivatives in all test systems. Specifically, 7 was shown to be about twice as potent as 3 in the murine spleen cell mitogenicity assay. In addition, treatment with 7 produced about a 4-fold increase in natural killer cell cytotoxicity, while treatment with 3 afforded a 3-fold increase over controls. Finally, 7 provided excellent protection (92% survivors compared to 0% for placebo controls) against Semliki Forest virus in mice. Induction of interferon may account for the major mode of action of these guanosine analogues.

Adenosine↗
PubMed1976

Imidazo(1,2-c)pyrimidine nucleosides. Synthesis and biological evaluation of certain 1-(beta-D-arabinofuranosyl)imidazo(1,2-c)pyrimidines.

The first chemical syntheses of the arabinosylhypoxanthine and arabinosylguanine analogues of the imidazo-[1,2-c]pyrimsdine series are described. Condensation of trimethylsilyl-7-chloroimidazo[1,2-c]pyrimidin-5-one (1) with 2,3,5-tri-O-benzyl-alpha-D-arabinofuranosyl chloride (2) gave 7-chloro-1-(2,3,5-tri-O-benzyl-beta-arabinofuranosyl)imidazo[1,2-c]pyrimidin-5-one (3) which on catalytic dehalogenation furnished 1-(2,3,5-tri-O-benzyl-beta-D-arabinofuranosyl)imidazo[1,2-c]pyrimidin-5-one (4). Amination of 3 gave 7-amino-1-(2,3,5-tri-O-benzyl-beta-D-arabinofuranosyl)imidazo[1,2-c]pyrimidin-5-one (5). Reductive hydrogenolysis of 4 and 5 gave 1-(betaD-arabinofuranosyl)imidazo[1,2-c]pyrimidin-5-one (6), the arabinosylhypoxantine analogue, and the corresponding 7-amino isomer 7, the arabinoosylguanine analogue, respectively. The unequivocal assignment of the site of glycosylation and the anomeric configuration have been established. None of the compounds exhibited significant antiviral or antimicrobial activity in vitro.

Anti-Bacterial Agents↗
PubMed1984

Synthesis and antiallergy activity of 10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidines and 10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidines.

Synthesis and antiallergy activity of 10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidines (2 and 3) and 10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidines (4 and 5) are described. The activity, shown by these compounds in the rat passive cutaneous anaphylaxis (PCA) test, is compared to the PCA data previously reported for a series of 4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidines. 10-Oxo-N-1H-tetrazol-5-yl-10H-pyrido[1,2-a]thieno[3,4-d]pyri midine (2b), 10-oxo-7-(1H-tetrazol-5-yl)-10H-pyrido[1,2-a]thieno[3,4-d]py rimidine (4e), and 3,10-dihydro-10-oxo-7-(1H-tetrazol-5-yl)-1H-pyrido[1,2-a]thieno[3, 4-d] pyrimidine (7e) gave a 100% inhibition in the rat PCA test at a dose of 5 mg/kg. The activity displayed by these compounds is comparable to that of the most active compounds in the 4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine series.

Animals↗
PubMed2005

Synthesis of N-{4-[(2,4-diamino-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic acid and N-{4-[(2-amino-4-oxo-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic acid as dual inhibitors of dihydrofolate reductase and thymidylate synthase and as potential antitumor agents.

Two novel classical antifolates N-{4-[(2,4-diamino-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic acid 3 and N-{4-[(2-amino-4-oxo-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic acid 4 were designed, synthesized, and evaluated as antitumor agents. Compounds 3 and 4 were obtained from 2,4-diamino-5-methylpyrrolo[2,3-d]pyrimidine 7 and 2-amino-4-oxo-5-methylpyrrolo[2,3-d]pyrimidine 12, respectively, in a concise three-step sequence. Compound 3 is the first example, to our knowledge, of a 2,4-diamino classical antifolate that has potent inhibitory activity against both human dihydrofolate reductase (DHFR) and human thymidylate synthase (TS). Compound 4 was a dual DHFR-TS inhibitor against the bifunctional enzyme derived from Toxoplasma gondii (tg). Further evaluation of the mechanism of action of 3 implicated DHFR as its primary intracellular target. Both 3 and 4 were folylpolyglutamate synthetase (FPGS) substrates. Compound 3 also inhibited the growth of several human tumor cell lines in culture with GI50 < 10(-8) M. This study shows that the pyrrolo[2,3-d]pyrimidine scaffold is conducive to dual DHFR-TS and tumor inhibitory activity, and the potency is determined by the 4-position substituent.

Animals↗
PubMed2003

A new and efficient synthesis of pyrrolo[2,3-d]pyrimidine anticancer agents: Alimta (LY231514, MTA), homo-Alimta, TNP-351, and some aryl 5-substituted pyrrolo[2,3-d]pyrimidines.

Alimta, as well as homo-Alimta, a nonbridged analogue of Alimta, and TNP-351 have been prepared by a new method that involves Michael addition of the appropriate 1-nitroalkene with 2,6-diamino-3H-pyrimidin-4-one or 2,4,6-triaminopyrimidine, followed by a Nef reaction of the resulting primary nitro Michael adduct. Spontaneous intramolecular cyclization of the resulting aldehyde with the pyrimidine 6-amino group yields the corresponding pyrrolo[2,3-d]pyrimidine. A series of previously unknown 5-arylpyrrolo[2,3-d]pyrimidines was prepared by the same methodology from the above pyrimidines and nitrostyrenes. It has been found that the intermediate primary nitro Michael adduct can be prepared in a single step by sonication of a mixture of an arylaldehyde, nitromethane, and the 6-aminopyrimidine in acetic acid containing ammonium acetate.

Antineoplastic Agents↗
PubMed2005

Inhibition of de novo pyrimidine synthesis in growing potato tubers leads to a compensatory stimulation of the pyrimidine salvage pathway and a subsequent increase in biosynthetic performance.

Pyrimidine nucleotides are of general importance for many aspects of cell function, but their role in the regulation of biosynthetic processes is still unclear. In this study, we investigate the influence of a decreased expression of UMP synthase (UMPS), a key enzyme in the pathway of de novo pyrimidine synthesis, on biosynthetic processes in growing potato (Solanum tuberosum) tubers. Transgenic plants were generated expressing UMPS in the antisense orientation under the control of the tuber-specific patatin promoter. Lines were selected with markedly decreased expression of UMPS in the tubers. Decreased expression of UMPS restricted the use of externally supplied orotate for de novo pyrimidine synthesis in tuber tissue, whereas the uridine-salvaging pathway was stimulated. This shift in the pathways of UMP synthesis was accompanied by increased levels of tuber uridine nucleotides, increased fluxes of [(14)C]sucrose to starch and cell wall synthesis, and increased amounts of starch and cell wall components in the tubers, whereas there were no changes in uridine nucleotide levels in leaves. Decreased expression of UMPS in tubers led to an increase in transcript levels of carbamoylphosphate synthase, uridine kinase, and uracil phosphoribosyltransferase, the latter two encoding enzymes in the pyrimidine salvage pathways. Thus, the results show that antisense inhibition of the de novo pathway of pyrimidine synthesis leads to a compensatory stimulation of the less energy-consuming salvage pathways, probably via increased expression and activity of uridine kinase and uracil phosphoribosyltransferase. This results in increased uridine nucleotide pool levels in tubers and improved biosynthetic performance.

Down-Regulation↗
PubMed1991

Inhibition of hexose monophosphate shunt in young erythrocytes by pyrimidine nucleotides in hereditary pyrimidine 5' nucleotidase deficiency.

Recent reports have suggested that haemolytic anaemia in pyrimidine 5' nucleotidase (P5'N) deficiency might be due to impaired erythrocyte hexose monophosphate shunt (HMS). To investigate the relationship between pyrimidine accumulation, HMS impairment and shortened red-cell survival, we tested glucose 6-phosphate dehydrogenase (G-6PD), HMS, P5'N activities and the UV spectrum in whole red cells and in red cells of different age from 2 P5'N-deficient patients with different degrees of haemolytic anaemia. In whole red cells we found a reduction of both G-6PD and stimulated HMS activity in the presence of a variable amount of pyrimidine nucleotides (37.79 and 17.88 mumol/gHb respectively). A drastic inhibition of stimulated HMS activity was already present in the lightest red-cell fractions from patient 1, who presented a more severe haemolytic anaemia. The variable degree of pyrimidines found among red cell fractions, with a minor accumulation in the older red cells, supports the hypothesis that pyrimidine accumulation and HMS impairment occur in the younger erythrocytes of P5'N-deficient patients.

5'-Nucleotidase↗
PubMed1970

Pyrimidine pools and macromolecular composition of pyrimidine-limited Escherichia coli.

The growth rate of a pyrimidine-requiring strain was controlled by limiting the concentration of exogenous orotic acid. As the steady state, pyrimidine-limited growth rate was decreased, the intracellular pyrimidine pools and the total nucleic acid per unit mass of culture also decreased. The ratio of deoxyribonucleic acid to protein remained constant, whereas the ratio of ribonucleic acid to protein decreased 30% over a threefold variation in growth rate (50- to 150-min doubling times). The intracellular uridine triphosphate and cytosine triphosphate pools also decreased (although not coordinately), and the pyrimidine biosynthetic enzymes were derepressed. Cell size was unaffected by pyrimidine-mediated variation of the growth rate.

Bacterial Proteins↗
PubMed2005

Analysis of pyrimidine catabolism in Drosophila melanogaster using epistatic interactions with mutations of pyrimidine biosynthesis and beta-alanine metabolism.

The biochemical pathway for pyrimidine catabolism links the pathways for pyrimidine biosynthesis and salvage with beta-alanine metabolism, providing an array of epistatic interactions with which to analyze mutations of these pathways. Loss-of-function mutations have been identified and characterized for each of the enzymes for pyrimidine catabolism: dihydropyrimidine dehydrogenase (DPD), su(r) mutants; dihydropyrimidinase (DHP), CRMP mutants; beta-alanine synthase (betaAS), pyd3 mutants. For all three genes, mutants are viable and fertile and manifest no obvious phenotypes, aside from a variety of epistatic interactions. Mutations of all three genes disrupt suppression by the rudimentary gain-of-function mutation (r(Su(b))) of the dark cuticle phenotype of black mutants in which beta-alanine pools are diminished; these results confirm that pyrimidines are the major source of beta-alanine in cuticle pigmentation. The truncated wing phenotype of rudimentary mutants is suppressed completely by su(r) mutations and partially by CRMP mutations; however, no suppression is exhibited by pyd3 mutations. Similarly, su(r) mutants are hypersensitive to dietary 5-fluorouracil, CRMP mutants are less sensitive, and pyd3 mutants exhibit wild-type sensitivity. These results are discussed in the context of similar consequences of 5-fluoropyrimidine toxicity and pyrimidine catabolism mutations in humans.

Amidohydrolases↗
PubMedDate not supplied

Synthesis of some new pyrimidine and fused pyrimidine derivatives (Part I).

2-Hydroxy- and 2-Mercapto-3,4-dihydro-4-oxo-6-(furyl)-pyrimidine-5-carbonitriles (3a, b) were synthesized by two different routes. Methylation of 3a with methyl iodide gave the S-methyl derivative 4, which could also be prepared by two other different methods. The reaction of 4 with phosphorous oxychloride yielded the 4-chloro-pyrimidine derivative 6, which reacted with hydrazine hydrate, aroylhydr-azines, thiourea and phenylhydrazine to form the tetra-substituted pyrimidine derivative (8), the triazolopyrimidine derivatives (14a, b), the mercapto compound 7 and the pyrazolo[3,4-d]pyrimidine derivative 11, respectively. Compound 7 reacted with chloroacetone and gave 15 which reacted with aromatic aldehydes affording the tricyclic compounds (16a, b). Reaction of 8 with carbon disulphide and/or nitrous acid yielded the pyrazolo[3,4-d]-S-triazolo-[3,4-d]pyrimidine 13 and 12, respectively.

Indicators and Reagents↗
PubMed2006

Synthesis and biological evaluation of some pyrimidine, pyrimido[2,1-b][1,3]thiazine and thiazolo[3,2-a]pyrimidine derivatives.

4,6-Diamino-1H-pyrimidine-2-thione (1) was used for the preparation of pyrimidine derivatives 2-5. Compound 5 was cyclized to produce pyrimido[2,1-b][1,3]thiazine derivative 6 which was condensed with p-chlorobenzaldehyde to give compound 7. The latter compound was reacted with hydroxylamine to give isoxazolo[4,5-d]thiazino[2,3-a]pyrimidine 8. Compound 8b was treated with 2-chloroethyl methyl ether to afford compound 9. Similarly, compound 3 reacted with chloroacetic acid to give thiazolo[3,2-a]pyrimidine 10, which was condensed with p-chlorobenzaldehyde to give compound 11. Compound 11 was condensed with hydroxylamine to give isoxazolo[4,5-d]thiazolo[2,3-a]pyrimidine 12. Compound 12b was treated with 2-chloroethyl methyl ether to afford compound 13. Biological evaluation of some prepared products showed that many of them revealed promising antimicrobial activity.

Anti-Infective Agents↗
PubMed1998

Adenosine 3':5'-cyclic monophosphate (cAMP)-inducible pyrimidine 5'-nucleotidase and pyrimidine nucleotide metabolism of chick embryonic erythrocytes.

Terminally differentiating erythrocytes degrade most of their RNA with subsequent release of mononucleotides. Pyrimidine mononucleotides are preferentially cleaved by an erythrocyte-specific pyrimidine 5'-nucleotidase; deficiency of this enzyme causes hemolytic anemia in humans. Details of the regulation of its activity during erythroid differentiation are unknown. The present study arose from the observation that the immature red blood cells (RBCs) of mid-term chick embryos contain high concentrations of uridine 5'-triphosphate (UTP) (5 to 6 mmol/L), which decline rapidly from days 13 to 14 onward. We analyzed two key enzymes of RBC pyrimidine nucleotide metabolism: pyrimidine nucleoside phosphorylase (PNP) and pyrimidine 5'-nucleotidase (P-5'-N), to evaluate if changes of enzyme activity during embryonic development are correlated with changes of RBC UTP. Secondly, we tested if these enzymes are under hormonal control. The results show that embryonic RBCs contain only minimal activity of PNP. In contrast, P-5'-N increases from day 13 on, suggesting that the enzyme is a limiting factor in UTP degradation. Activation of beta-adrenergic and A2A-adenosine receptors causes transcription-dependent de novo synthesis of P-5'-N. Because beta-adrenergic and adenosine receptors are also found on adult erythroid cells, P-5'-N might be an enzyme of differentiating RBCs whose expression is in part controlled by adenosine 3':5'-cyclic monophosphate (cAMP).

5'-Nucleotidase↗
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↗
PubMed2001

Ferromagnetic exchange coupling of vanadium(IV) dpi spins across pyrimidine rings: dinuclear complexes of oxovanadium(IV) bis(1,1,1,5,5,5-hexafluoropentane-2,4-dionate) bridged by pyrimidine derivatives.

Dinuclear oxovanadium(IV) complexes bridged by pyrimidine derivatives, L[VO(hfac)(2)](2) [L = pyrimidine (PM), 4-methylpyrimidine (MPM), 4,6-dimethylpyrimidine, 4-aminopyrimidine, and quinazoline; hfac = 1,1,1,5,5,5-hexafluoropentane-2,4-dionate], were synthesized and characterized. All of them showed intramolecular ferromagnetic interaction, and the magnetic susceptibilities were analyzed on the basis of the singlet-triplet model, giving 2J/k(B) = 2.2-5.5 K. PM[VO(hfac)(2)](2) crystallized in a monoclinic space group C2/c with a = 34.092(2), b = 6.9783(4), and c = 16.4940(9) A, beta = 109.104(1) degrees, V = 3707.8(4) A(3), and Z = 4 for C(24)H(8)F(24)N(2)O(10)V(2), and MPM[VO(hfac)(2)](2) gave isomorphous crystals. A semiempirical calculation study based on the determined structure suggests the presence of dpi-ppi interaction between vanadium and pyrimidine nitrogen atoms. Ferromagnetic coupling is explained in terms of a spin-polarization mechanism across the pyrimidine bridge. The intermolecular ferromagnetic interaction of PM[VO(hfac)(2)](2) can be interpreted by the contact between the spin-polarized pyrimidine moiety and the oxovanadium oxygen atom in an adjacent molecule.

Journal Article↗
PubMed1996

Possible prediction of adverse reactions to pyrimidine chemotherapy from urinary pyrimidine levels and a case of asymptomatic adult dihydropyrimidinuria.

Deficiency of dihydropyrimidine dehydrogenase or dihydropyrimidinase, enzymes that catalyze the breakdown of pyrimidine chemotherapy agents such as 5-fluorouracil, may cause serious adverse reactions to these agents. We attempted to establish the reference range for urinary pyrimidines in adults to detect individuals with abnormal pyrimidine metabolism. We analyzed urinary pyrimidine levels in 1133 adults to establish a reference range for persons ages 20 years or older. Urinary dihydrouracil and uracil levels were determined by high-performance liquid chromatography with column switching. The reference range obtained was found to be 0-59.3 micromol/g creatinine for dihydrouracil and 0-129.8 micromol/g creatinine for uracil. In addition, an asymptomatic man with suspected dihydropyrimidinase deficiency was detected on the basis of dihydropyrimidinuria. Although only three cases of this disease have been found worldwide, including one infant reported previously by our group, it may not be so rare as has been thought. In this man, a 10 mg/kg oral uracil loading test yielded a peak blood dihydrouracil level of 192.1 micromol/liter and a peak uracil level of 67.8 micromol/liter. Eight h after loading, the uracil level was still 11.1 micromol/liter, about 17 times that in healthy subjects. Additional research on dihydropyrimininase deficiency may help to prevent adverse reactions to pyrimidine chemotherapy agents in susceptible individuals.

Adult↗
PubMed1995

Photo-CIDNP study of pyrimidine dimer splitting. I: Reactions involving pyrimidine radical cation intermediates.

The light-induced splitting of pyrimidine dimers was studied using the electron acceptor anthraquinone-2-sulfonate (AQS) as a photosensitizer. To this end, photochemically induced dynamic nuclear polarization (photo-CIDNP) experiments were performed on a series of pyrimidine monomers and dimers. The CIDNP spectra demonstrate the existence of both the dimer radical cation, which is formed by electron transfer from the dimer to the photoexcited sensitizer AQS*, and its dissociation product, the monomer radical cation. In spectra of 1,1'-trimethylene bridged cis, syn pyrimidine dimers, polarization is observed that originates from a spin-sorting process in the dimer radical pair. This points to a relatively long lifetime of the dimer radical cation involved, which is presumably due to stabilization by the trimethylene bridge. Polarization originating from a dimer radical pair is detected in the spectrum of trans,anti (1,3-dimethyluracil) dimer as well. The spectra of the bridged pyrimidines also demonstrate the reversibility of the dissociation of dimer radical cation into monomer radical cation, which is concluded from the observation of polarization in the dimer as a result of spin sorting in the monomer radical pair.

Cations↗