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PubMed1982

Adenosine- and deoxyadenosine-mediated altered pyrimidine metabolism in human adeosine deaminase-deficient lymphoblasts.

To evaluate the importance of altered pyrimidine synthesis in the relationship between immune dysfunction and deficiency of ADA, this pathway has been evaluated in normal and ADA-deficient human lymphoblasts. Adenosine and deoxyadenosine effect comparable reductions of radiolabeled bicarbonate incorporation in uridine nucleosides of both normal and deficient cells, with this effect being more prolonged in deficient cells. In ADA-deficient lymphoblasts this altered pyrimidine metabolism is accompanied by reduced intracellular concentrations of PP-ribose-P with adenosine but not deoxyadenosine. The altered PP-ribose-P levels are accompanied by orotic acid accumulation, but this block does not fully account for the net reduction in uridine nucleotide synthesis. This suggests interference of the pyrimidine pathway at another locus, possibly by altered carbamyl phosphate synthetase activity. The mechanism for deoxyadenosine-mediated inhibition is obscure. Despite the demonstrable adenosine- and deoxyadenosine-mediated alterations of pyrimidine metabolism, these changes are not accompanied by marked interference of cell growth for both normal and ADA-deficient lymphoblasts. These data support the hypothesis that altered pyrimidine metabolism is not the basis for the immune disorder in patients with deficiency of ADA.

Adenosine↗

PubMed1981

Photoreactivation of ultraviolet radiation-induced pyrimidine dimers in neonatal BALB/c mouse skin.

The numbers of ultraviolet light (UV)-induced pyrimidine dimers in the DNA of neonatal BALB/c mouse skin were measured by assessing the sensitivity of the DNA to Micrococcus luteus UV endonuclease. Irradiation of neonatal BALB/c mice with FS40 sunlamps caused a dose-dependent induction of endonuclease-sensitive sites (pyrimidine dimers) in DNA extracted from back skin. Exposure of these UV-irradiated neonatal mice to photoreactivating (PR) light ("cool white" fluorescent lamp and incandescent lamp) caused a reduction in the number of pyrimidine dimers in the DNA, as revealed by a shift in low-molecular-weight DNA to high-molecular-weight DNA. In contrast, DNA profiles of the skin of either UV-irradiated mice or UV-irradiated mice kept in the dark for the same duration as those exposed to PR light did not show a loss of UV-induced endonuclease-sensitive sites. Furthermore, reversing the order of treatment, i.e., administering PR light first and then UV, did not produce a reduction in pyrimidine dimers. These results demonstrate that PR or UV-induced pyrimidine dimers occurs in neonatal BALB/c mouse skin. The optimal wavelength range for in vivo PR appears to be in the visible region of the spectrum (greater than 400 nm). Although dimer formation could be detected in both dermis and epidermis, PR occurred only in the dermis. Furthermore, the PR phenomenon could not be detected in the skin of adult mice from the same inbred strain.

Age Factors↗

PubMed1995

Probing the conformation of nucleosome linker DNA in situ with pyrimidine dimer formation.

The distribution of pyrimidine dimers formed in nucleosomal DNA by irradiation of intact nuclei isolated from rat liver has been examined. Whereas pyrimidine dimer formation in the core region of the nucleosome occurred with peaks at approximately 10-nucleotide intervals as previously reported, the distribution of pyrimidine dimers through the linker region was nearly uniform. This distinction between core and linker DNA was found to be independent of linker length over a range of 38-60 nucleotides. Because there is now ample evidence that DNA curvature is the source of the peaks of pyrimidine dimer formation in the core region, the uniform distribution of pyrimidine dimers observed in the linker region indicates that linker DNA is relatively straight. This suggests that higher order chromatin structure in situ is based on a zigzag chain of nucleosomes.

Animals↗

PubMed1997

Metabolism and excretion of a new antianxiety drug candidate, CP-93,393, in cynomolgus monkeys: identification of the novel pyrimidine ring cleaved metabolites.

The metabolism and excretion of a new anxiolytic/antidepressant drug candidate, CP-93,393, ((7S, 9aS)-1-(2-pyrimidin-2-yl-octahydro-pyrido[1, 2-a]-pyrazin-7-yl-methyl)-pyrrolidine-2,5-dione) were investigated in cynomolgus monkeys after oral administration of a single 5 mg/kg dose of 14C-CP-93,393. Urine, bile, feces, and blood samples were collected and assayed for total radioactivity, parent drug, and metabolites. Total recovery of the administered dose after 6 days was 80% with the majority recovered during the first 48 hr. An average of 69% of the total radioactivity was recovered in urine, 4% in bile, and 7% in feces. Mean Cmax and AUC(0-infinity) values for the unchanged CP-93,393 were 143.2 ng/ml and 497.7 ng.hr/ml, respectively, in the male monkeys and 17.2 ng/ml and 13.7 ng.hr/ml, respectively, in the female monkeys. HPLC analysis of urine, bile, feces, and plasma from both male and female monkeys indicated extensive metabolism of CP-93,393 to several metabolites. The identification of metabolites was achieved by chemical derivatization, beta-glucuronidase/sulfatase treatment, and by LC/MS/MS, and the quantity of each metabolite was determined by radioactivity detector. CP-93,393 undergoes metabolism by three primary pathways, aromatic hydroxylation, oxidative degradation of the pyrimidine ring, and hydrolysis of the succinimide ring followed by a variety of secondary pathways, such as oxidation, methylation, and conjugation with glucuronic acid and sulfuric acid. The major metabolites, oxidation on the pyrimidine ring to form 5-OH-CP-93,393 (M15) followed by glucuronide and sulfate conjugation (M7 and M13), accounted for 35-45% of the dose in excreta. Two metabolites (M25 and M26) were formed by further oxidation of M15 followed by methylation of the resulting catechol intermediate presumably by catechol-O-methyl transferase. A novel metabolic pathway, resulting in the cleavage of the pyrimidine ring, was also identified. The metabolites (M18, M20, and M21) observed from this pathway accounted for 8-15% of the dose. Aliphatic hydroxylation of the succinimide ring was a very minor pathway in monkey. 5-Hydroxy-CP-93,393 (M15, 37-49%), its sulfate and glucuronide conjugates (M7 and M13, approximately 34%), and the pyrimidine ring cleaved product (M18, approximately 8%) were the major metabolites in monkey plasma. The identified metabolites accounted for approximately 90, 93, 97, and 92% of the total radioactivity present in urine, bile, plasma, and feces, respectively. The major in vivo oxidative metabolites were also observed after in vitro incubations with monkey liver microsomes.

Adrenergic alpha-2 Receptor Antagonists↗

PubMed1998

[Synthesis and properties of 5(4,6-diphenyl-2-pyrimidin-2-yl)-1,2,4-triazolin-3-thione and derivatives ].

By treatment of 4,6-diphenyl-pyrimidin-2-carboxyl chloride (1) with thiosemicarbazide the acylthiosemicarbazide 3 has been synthesized. Compound 3 could also be obtained by action of hydrazide on potassium thiocyanate. 5-(4,6-Diphenyl-pyrimidin-2-yl)-1,2,4-triazolin-3-thione (5) could be prepared either by basecatalyzed cyclization of acylthiosemicarbazide or by the reaction of methyl 4,6-diphenyl-pyrimidin-2-carboxylate with thiosemicarbazide in the presence of sodium methoxide. Alkylation of the 1,2,4-triazolin-3-thione 5 with chloroacetic acid resulted in formation of the S-carboxymethyl derivative 6. On heating, with a mixture of glacial acetic acid/acetic anhydride, compound 6 afforded 6-(4,6-diphenyl-pyrimidin-2-yl)thiazolo[3,2-b]-1,2,4-triazol-3(2H) -one (7). Condensation of 7 with aromatic aldehydes yielded 2-arylidene-6-(4,6-diphenyl-pyrimidin-2-yl)thiazolo[3,2-b]-1,2,4-+ ++triazol-3(2H)-ones, which could also be prepared by treatment of the S-carboxymethyl derivative 6 with an appropriate aldehyde in the presence of acetic acid and acetic anhydride. Some of the synthesized compounds possess a weak antiinflammatory activity.

Animals↗

PubMed1998

[Antimicrobial activity of some derivatives of pyrimidine].

In this paper the authors present the antimicrobial and antifungical tests of some new 3-methylpyrimidine compounds. The test was performed using the diffusimetric method with rustlessteel cylinders based on the diffusion of the tested substances on the gelose surface. The comparative analysis of the obtained data leads to the following conclusions concerning the relation between structure and biological activity in the pyrimidine series: 1. The pyrimidinium ylides are less active comparatively with the corresponding salts. That means that the zwitter ionic structure did not favour the activity. 2. Comparative with the corresponding pyridazine(1,2-diazine) derivatives, the pyrimidine(1,3-diazine) compounds are more active. The increase of activity of the pyrimidine compounds could be attributed of the influence of the pyrimidine ring. 3. The most active pyrimidine compound which is tested is that one in which radical R is an amide group. 4. In the case when the radical R is a phenyl ring, the substitute from para position of benzoylic radical does not appear decisive towards activity, these affecting especially the selectivity.

Anti-Bacterial Agents↗

PubMed1983

Pyrimidine metabolism in Tritrichomonas foetus.

The anaerobic parasitic protozoa Tritrichomonas foetus is found incapable of de novo pyrimidine biosynthesis by its failure to incorporate bicarbonate, aspartate, or orotate into pyrimidine nucleotides or nucleic acids. Uracil phosphoribosyltransferase in the cytoplasm provides the major pyrimidine salvage for the parasite. Exogenous uridine and cytidine are mostly converted to uracil by uridine phosphorylase and cytidine deaminase in T. foetus prior to incorporation. T. foetus cannot incorporate labels from exogenous uracil or uridine into DNA; it has no detectable dihydrofolate reductase or thymidylate synthetase and is resistant to methotrexate, pyrimethamine, trimethoprim, and 5-bromovinyldeoxyuridine at millimolar concentrations. It has an enzyme thymidine phosphotransferase in cellular fraction pelleting at 100,000 X g that can convert exogenous thymidine to TMP via a phosphate donor such as p-nitrophenyl phosphate or nucleoside 5'-monophosphate. Thymidine salvage in T. foetus is thus totally dissociated from other pyrimidine salvage.

Animals↗

PubMed1995

Structure-activity relationship of a pyrimidine receptor in the rat isolated superior cervical ganglion.

1. The effects of pyrimidines and purines on the d.c. potential of the rat isolated superior cervical ganglion (SCG) have been examined by a grease-gap technique to determine the structure-activity requirements of the receptor activated by pyrimidines, i.e. a pyrimidinoceptor. 2. 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranosyl (ZTP), the pyrimidines, cytidine 5'-triphosphate (CTP), uridine 5'-triphosphate (UTP) and thymidine 5'-triphosphate (TTP) and the purines, adenosine 5'-triphosphate (ATP; in the presence of an A1-purinoceptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) (1 microM)), adenosine 5'-O-(3-thiotriphosphate) (ATP gamma S), guanosine 5'-triphosphate (GTP), inosine 5'-triphosphate (1TP) depolarized ganglia in a concentration-dependent manner. The relative order of ZTP and purine 5'-triphosphates in depolarizing ganglia was ZTP > or = ATP gamma S > > ATP > or = ITP = GTP, and for the pyrimidine 5'-triphosphates UTP > TTP > or = CTP. Depolarizations evoked by ATP gamma S were followed by concentration-dependent hyperpolarizations at 100 and 1000 microM. 3. At concentrations of between 0.1 microM and 1 mM, uridine 5'-diphosphate (UDP), uridine 5'-diphosphoglucose (UDPG) and uridine 5'-diphosphoglucuronic acid (UDPGA) evoked significant and concentration-dependent depolarizations, whereas uridine 5'-monophosphate (UMP), uridine and uracil were inactive or produced small (< 45 microV) depolarizations. The relative order of potency of uridine analogues in depolarizing ganglia was UDP > or = UTP > UDPG > UDPGA > > uracil > or = UMP = pseudouridine > or = uridine. At 3 and 10 mM, uridine produced concentration-dependent hyperpolarizations. Nikkomycin Z, a nucleoside resembling UTP (viz. the triphosphate chain at the 5'-position on the ribose moiety being replaced by a peptide), was inactive between 1 microM and 1 mM. Generally, a concentration of 10 mM was required before thymidine, 6-azathymine, 6-azauracil or 6-azauridine depolarized ganglia. 4. Suramin (300 microM), a P2-purinoceptor antagonist, significantly depressed depolarizations evoked by alpha, beta-methylene-ATP (alpha, beta-MeATP; 100 microM), ATP gamma S (100 microM), CTP (1 mM), GTP (1 mM), ZTP (30 microM) and ATP (300 microM) in the presence of DPCPX (1 microM). Suramin reversed a small depolarization evoked by UMP (1 mM) into a small hyperpolarization. In contrast depolarizations evoked by UDP, UTP, UDPG (all at 100 microM) and TTP (300 microM) were unaltered or enhanced by suramin. 5. It is concluded that the rat SCG contains distinct nucleotide receptors including a P2-purinoceptor (activated by alpha, beta-MeATP, ATP, GTP, ITP and ZTP) and a pyrimidinoceptor (activated by UTP, UDP, UDPG, UDPGA and TTP). The pyrimidinoceptor on rat SCG neurones had specific structure activity requirements with the di- and triphosphates of uridine being the most effective depolarizing agonists examined.

Aminoglycosides↗

PubMed1975

[Disorders of human pyrimidine metabolism (author's transl)].

Pyrimidine synthesis and its regulation are presented. Among the disorders of human pyrimidine metabolism, hereditary orotic aciduria and that produced by drugs play the principal role. A rise in renal excretion of orotic acis is also observed when ornithine transcarbamylase activity is lacking. The importance of "orotic aciduria with partial response to folic acid" in pyrimidine metabolism is still not clear. Close relationship between the formation of pyrimidine and purine nucleotides must be assumed, because both enter into the synthesis of nucleic acid, for the greatest part in approximately equimolecular amounts. Possibly 5-phosphoribosyl-1-pyrophosphate plays an important part.

Allopurinol↗

PubMed1984

Effect of guanosine on antitumor activity of fluorinated pyrimidines against P 388 leukemia.

The antitumor activity of the fluorinated pyrimidines 5-fluorouracil (FUra), 5-fluorouridine (FUrd), and 5-fluoro-2'-deoxyuridine (FdUrd) against P388 leukemia was markedly potentiated by the addition of guanosine (Guo), resulting in therapeutic synergism. Any combination of FUra at 1-20 mg/kg, FUrd at 0.3-1 mg/kg, or FdUrd at 1-100 mg/kg with Guo at 100 mg/kg significantly potentiated the activity of FUra, FUrd, or FdUrd, respectively. The potentiation of these fluorinated pyrimidines by guanosine was abolished by the simultaneous administration of cytidine or uridine, but not of thymidine. In particular, cytidine was the strongest inhibitor of antitumor activity of these fluorinated pyrimidines, alone and in combination with guanosine. To obtain more effective treatment with the combination of various fluorinated pyrimidines and Guo, the influence of the molar ratios of Guo to the fluorinated pyrimidines on the antitumor activity against P388 leukemia was investigated. The increase in life-span became more pronounced with increasing molar ratios. The optimal molar ratios of Guo/FUra, Guo/FUrd, and Guo/FdUrd were more than 5, 100, and 5, respectively.

Animals↗

PubMed2006

Synthesis of some new bioactive 3-amino-2-mercapto-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-one derivatives.

Nine new 2-(substituted phenyl)/alkyl[1,3,4]thiadiazolo[2,3-b]-6,7,8,9-tetrahydrobenzo(b)thieno[3,2-e]pyrimidin-5(4H)-ones, six new 3-amino-2-[(2-oxo-2-(aryl)ethyl)thio]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-ones, one 2-mercapto[1,3,4]thiadiazolo[2,3-b]-6,7,8,9-tetrahydrobenzo(b)thieno[3,2-e]pyrimidin-5(4H)-one and one 2-chloromethyl[1,3,4]thiadiazolo[2,3-b]-6,7,8,9-tetrahydrobenzo(b)thieno[3,2-e]pyrimidin-5(4H)-one were synthesized from 3-amino-2-mercapto-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-one. The newly synthesized compounds were characterized by analytical and spectral data. Compounds were screened for anti-inflammatory, CNS depressant and antimicrobial activities. Some of the compounds exhibited promising biological activities.

Animals↗

PubMed1998

Crystal structures of 5-fluoro-dUrd and its 2 and/or 4-thio analogues: models of substituted dUMP pyrimidine ring interacting with thymidylate synthase.

In order to understand the influence on thymidylate synthase interactions with dUMP analogues of the pyrimidine ring 2- and/or 4-thio, and 5-fluoro substitutions, X-ray diffractions by crystals of 5-fluoro-dUrd and its 2- and 4-thio, and 2,4-dithio analogues were measured, the four structures solved and refined. The following conclusions were suggested by results of comparative analyses of structural parameters (bond lengths, valence angles), followed by theoretical considerations based on calculated resonance structure distributions and aromaticity indices of the uracil, thiouracil, fluorouracil and fluorothiouracil rings. The effect of 4-thio substitution of FdUMP, altering specificity of inactivation of thymidylate synthases from various sources, is probably due to weaker proton acceptor power of the 4-thio substituent and increasing acidity (enhanced proton-donor power) of the N(3)-H moiety, resulting in an impaired fitness into the network of hydrogen bonds in the enzyme active center cleft. 2,4-Dithio substitution results in (i) impaired pyrimidine ring recognition by the enzyme active center, due to the 4-thio substituent (ii) increased pyrimidine ring aromaticity in dUMP, leading to resistance of C(6) to nucleophilic attack by the enzyme active center cysteine and (iii) altered planarity of the pyrimidine ring and deflections, with respect to the ring plane, of substituents at C(2), C(4) and C(5). 5-Fluoro substitution apparently activates the pyrimidine ring towards the interaction with thymidylate synthase by producing local strain, which results in an increased reactivity as predicted by the Walsh-Bent rule.

Binding Sites↗

PubMed1976

Synthesis and biological activity of pyrazolo[3,4,-d]pyrimidine nucleosides and nucleotides related to tubercidin, toyocamycin, and sangivamycin.

The 6-aza analogues of toyocamycin and sangivamycin were prepared as potential cytotoxic agents. The toyocamycin analogue (4-amino-1-(beta-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine-3-carbonitrile) could not be obtained directly from its O-acetylated precursor but was accessible via 4-amino-1-(beta-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine-3-thiocarboxamide. The identity of the nitrile was verified by its ultraviolet, infrared, and mass spectra, and by its conversion to the corresponding 3-carboxamide and thiocarboxamide when treated with water or hydrogen sulfide, respectively. Bioassay of the synthetic compounds in comparison with 4-amino-1-(beta-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine (6-azatubercidin) and 4-amino-2-(beta-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine revealed that the 3-thiocarboxamido derivative was more cytotoxic to the growth of mouse fibroblasts than 6-azatubercidin, effecting killing of 3T6 cells at less than or equal to 1 mug/ml. 4-Amino-1-(beta-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine (but not its 2-ribofuranosyl isomer) was shown to act as a substrate for adenosine deaminase from calf intestinal mucosa with an apparent Km of 125 (vs. 20 for adenosine) and the corresponding 5'-diphosphate of 6-azatubercidin was polymerized by polynucleotide phosphorylase (Micrococcus luteus) in the presence of Mn2+ to afford a homopolymer and copolymers with adenosine. The copolymers directed the binding of [3H]lysyl-tRNA to the A-site of ribosomes from Escherichia coli, but could not be used for the synthesis of polylsine in a cellfree system. The copolymer consiting of adenosine and 6-azatubercidin in a 2:1 ratio was found to form a 1:1 complex with poly(uridylic acid) at 4degreesC.

Antibiotics, Antineoplastic↗

PubMedDate not supplied

Deazapurine solid-phase synthesis: combinatorial synthesis of a library of N3,N5,C6-trisubstituted pyrrolo[3,2-d]pyrimidine derivatives on cross-linked polystyrene bearing a cysteamine linker.

Solid-phase methodology for the preparation of pyrrolo[3,2-d]pyrimidine-6-carboxylates with diversity at the N3 pyrmidine nitrogen has now been elaborated to allow for the generation of pyrrolopyrimidine libraries with members possessing diversity at the N3, N5, and C6 positions. The diversification of the N5 position was achieved by treating the parent resin-bound pyrrolo[3,2-d]pyrimidines 3 with an alkyl halide in the presence of Cs2CO3 in DMF. Modification of the C6 carboxylate of resin-bound pyrrolopyrimidines 3-5 was first achieved by hydrolysis of the benzyl ester using LiOH in a mixture of THF/H2O/MeOH. Further alteration of the C6 position of resin-bound pyrrolo[3,2-d]pyrimidine-6-carboxylic acids 6-8 was then performed by activation with triphosgene and treatment with an amine to furnish resin-bound pyrrolo[3,2-d]pyrimidine-6-amides. Twenty-two pyrrolo[3,2-d]pyrimidines 1a-v with different substituents at the N3, N5, and C6 positions were obtained in yields of 21-83% and purities of 61-98% after cleavage from the solid support.

Journal Article↗

PubMed1988

Synthesis and antiviral activity of certain 4- and 4,5-disubstituted 7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidines.

In vitro evaluation of a series of previously prepared tubercidin analogues revealed that certain 5-halogen-substituted analogues were active against human cytomegalovirus (HCMV) at concentrations lower than those that produced comparable cytotoxicity in uninfected cells. In contrast, tubercidin was cytotoxic at all antiviral concentrations. Even though the antiviral selectivity of the 5-substituted compounds was slight, this observation led us to prepare a series of acyclic analogues. Treatment of the sodium salt of 4-chloropyrrolo[2,3-d]pyrimidine (2) with (2-acetoxyethoxy)methyl bromide (2a) provided the acyclic nucleoside 4-chloro-7-[(2-acetoxyethoxy)methyl]pyrrolo[2,3-d]pyrimidine (3). A nucleophilic displacement of the 4-chloro group with methoxide, methylamine, and dimethylamine yielded the corresponding 4-substituted compounds 4, 5, and 6, respectively, in good yield. Electrophilic substitution (chlorination, bromination, and iodination) was effected at the C-5 position of compound 3 with N-chlorosuccinimide, N-bromosuccinimide, and iodine monochloride, respectively, in methylene chloride. Removal of the acetyl group from these intermediates (7a-9a) with methanolic ammonia at room temperature afforded the 5-chloro (7b), 5-bromo (8b), and 5-iodo (9b) derivatives of 4-chloro-7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidine. Treatment of compounds 7b-9b with methanolic ammonia at an elevated temperature produced the corresponding 5-halotubercidin analogues 10, 11, and 12, respectively. An alternate procedure for the preparation of these 4,5-disubstituted 7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidines involved an electrophilic substitution prior to the condensation of the heterocycle with 2a. Treatment of 2 with N-chlorosuccinimide and N-bromosuccinimide gave compounds 13a and 13b, respectively. The condensation of 13a and 13b with 2a and subsequent treatment with methylamine and ethylamine furnished the corresponding 5-halo-4-substituted-pyrrolo[2,3-d]pyrimidines 14a, 14b, 14c, and 14d, respectively. Evaluation of the target compounds (4-6, 7b-9b, 10-12, and 14a-14d) for cytotoxicity and activity against HCMV and herpes simplex virus type 1 (HSV-1) revealed that all compounds except the 5-halogen-substituted compounds 10, 11, and 12 were inactive. Compounds 10, 11, and 12 were active against both viruses at noncytotoxic concentrations. The activity of compound 11 was particularly noteworthy, being at least 10-fold more potent than acyclovir.

Acyclovir↗

PubMed1990

Guanosine analogues. Synthesis of nucleosides of certain 3-substituted 6-aminopyrazolo[3,4-d]pyrimidin-4(5H)-ones as potential immunotherapeutic agents.

Several guanosine analogues were synthesized in the pyrazolo[3,4-d]pyrimidine ring system with various substituents at the 3-position. The new analogues prepared here include the CH3 (2-amino-3-methyl-1-beta-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-4 (5H)-one, 13a), the phenyl (2-amino-3-phenyl-1-beta-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-4 (5H)-one, 13b), and the NH2 (3,6-diamino-1-beta-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-4(5H)- one, 17) substituted derivatives. These new agents, as well as several other 3-substituted derivatives including H, Br, OCH3, COOH, and oxo, were evaluated for their ability to potentiate certain murine immune functions relative to the known active agent 5-amino-3-beta-D-ribofuranosylthiazolo[4,5-d]pyrimidine-2,7(3H,6H) -dione (4, 7-thia-8-oxoguanosine). The biological evaluation included the (1) ex vivo determination of increased natural killer cell function and (2) in vivo antiviral protection against a lethal challenge of Semliki Forest virus. The 3-unsubstituted (5a) and the 3-bromo (5c) derivatives were found to be the most active immunopotentiators in this series.

Adjuvants, Immunologic↗

PubMed1998

Diels-Alder Cycloadducts of [60]Fullerene with Pyrimidine o-Quinodimethanes.

Novel organofullerenes bearing a pyrimidine nucleus covalently attached to the C(60) cage have been prepared by [4 + 2] cycloaddition reactions of C(60) and pyrimidine o-quinodimethanes generated "in situ" from the readily available cyclobutapyrimidines which are prepared in a one-pot procedure from cyclobutanone and alkyl or aryl nitriles. The reaction mechanism involves formation of a nitrilium cation with participation of two molecules of the respective nitrile. A side-product (16) formed from two cyclobutanone molecules is obtained together with the target cyclobutapyrimidines 4a-d. Compounds 4a-d are appropriate precursors for the generation of substituted pyrimidine o-quinodimethanes 5a-d which are efficiently trapped by the C(60) molecule in a cycloaddition reaction which according to theoretical calculations is controlled by the HOMO of the diene. (1)H NMR spectra indicate the presence of a dynamic process attributed to the boat-to-boat interconversion of the cyclohexene ring. The activation free energy has been measured by dynamic NMR experiments showing values DeltaG() approximately 16-17 kcal/mol for both methylene groups, depending upon the substituents on the pyrimidine unit. Theoretical calculations at the semiempirical PM3 level confirm the presence of a boat conformation for the cyclohexene ring which undergoes a rapid flipping motion resulting in an average C(s)() symmetry as it is observed in the (1)H NMR spectra. The cyclic voltammetry measurements show the presence of reduction waves cathodically shifted, related to C(60), due to the saturation of a double bond of the C(60) cage. A weak electronic interaction is observed between the pyrimidine moiety and the C(60) core.

Journal Article↗

PubMed2005

First singlet (n,pi*) excited state of hydrogen-bonded complexes between water and pyrimidine.

Hydrogen bonds from water to excited-state formaldehyde and from water to excited-state pyridine have been shown to display novel motifs to traditional hydrogen bonds involving ground states, with, in particular for H2O:pyridine, strong interactions involving the electron-rich pi cloud dominating the (n,pi) excited state. We investigate H2O:pyrimidine and various dihydrated species and reveal another motif, one in which the hydrogen bonding can dramatically alter the electronic structure of the excited state. Such effects are rare for ground-state interactions for which hydrogen bonding usually acts to merely perturb the electronic structure of the participating molecules. It arises as the (n,pi*) excitation of isolated pyrimidine is delocalized over both nitrogens but asymmetric hydrogen bonding causes it to localize on just the noninteracting atom. As a result, the excited-state hydrogen bond in H2O:pyrimidine is suprisingly very similar to the ground-state structure. These results lead to an improved understanding of the spectroscopy of pyrimidine in liquid water, and to the prediction that stable excited-state hydrogen bonds in H2O:pyrimidine should be observable, despite failure of experiments to actually do so. They also provide a simple model for the intricate control over primary charge separation in photosynthesis exerted by hydrogen bonding, and for solvent-induced electron localization in symmetric mixed-valence complexes. All conclusions are based on strong parallels found between the results of calculations performed using density-functional theory (DFT) and time-dependent DFT (TDDFT), complete-active-space self-consistent-field (CASSCF) with second-order perturbation-theory correction (CASPT2) theory, and equation-of-motion coupled cluster (EOM-CCSD) theory, calculations that are verified through detailed comparison of computed properties with experimental data for both the isolated molecules and the ground-state hydrogen bond.

Journal Article↗