Uracil Nucleosides Research Articles

Palladium-catalyzed direct arylation of 5-halouracils and 5-halouracil nucleosides with arenes and heteroarenes promoted by TBAF.

The 1-N-benzyl-5-iodo(or bromo)uracil undergoes Pd-catalyzed [Pd2(dba)3] direct arylation with benzene and other simple arenes in the presence of TBAF in DMF without the necessity of adding any ligands or additives to give 5-arylated uracil analogues. The TBAF-promoted coupling also occurs efficiently with electron rich heteroarenes at 100 °C (1 h) even with only small excess of heteroarenes. The protocol avoids usage of the arylboronic acid or stannane precursors for the synthesis of 5-(2-furyl, or 2-thienyl, or 2-pyrrolyl)uracil nucleosides, which are used as important RNA and DNA fluorescent probes. The fact that 1-N-benzyl-3-N-methyl-5-iodouracil did not undergo the TBAF-promoted couplings with arenes or heteroarenes suggests that the C4-alkoxide (enol form of uracil) facilitates coupling by participation in the intramolecular processes of hydrogen abstraction from arenes. TBAF-promoted arylation was extended into the other enolizable heterocyclic systems such as 3-bromo-2-pyridone. The π-excessive heteroarenes also coupled with 5-halouracils in the presence of Pd(OAc)2/Cs2CO3/PivOH combination in DMF (100 °C, 2 h) to yield 5-arylated uracils.

A general approach to the synthesis of 5-S-functionalized pyrimidine nucleosides and their analogues.

A general and efficient approach was developed for the introduction of S-functionality at the C-5 position of cytosine and uracil nucleosides and their analogues. The key step is a palladium-catalyzed C-S coupling of the corresponding 5-bromo nucleoside derivative and alkyl thiol. The butyl 3-mercaptopropionate coupling products were further converted to the corresponding disulphides, the stable precursors of 5-mercaptopyrimidine nucleosides.

Local Transplant of Human Umbilical Cord Matrix Stem Cells Improves Skin Flap Survival in a Mouse Model

A skin flap is a piece of skin that has its own blood supply, which is useful to repair large skin defects and deep wounds in plastic surgery. However, partial skin flap necrosis usually occurred. Bone marrow mesenchymal stem cells (BM MSCs) are effective in improving the ischemic flap survival, but their clinical application is restricted by their limited source. Human umbilical cord matrix stem (HUCMS) cells are easily isolated in a large number, compared to BM MSCs. In this study, we evaluated the therapeutic potential of HUCMS to improve the survival of ischemic skin flap. HUCMS cells were characterized with surface markers, and were labeled with 5-acetylene base-2 'deoxidizing uracil nucleoside (EdU) in vitro. Twenty male immunodeficient BALB/c mice with an epigastric flap were randomly divided into two groups. HUCMS cells or Dulbecco's Modified Eagle Medium (DMEM) were injected into the subcutaneous flap tissues. On the 7th postoperative day, flap survival, capillary density, levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), and EdU-positive cells in the skin flap were examined. Results showed that flap survival rate was higher in the HUCMS cell group (P < 0.05). Capillary density, VEGF level, and bFGF level were higher in the HUCMS cell group (P < 0.05). EdU-labeled HUCMS cells were mainly distributed in the subcutaneous flap tissues. These findings suggest that HUCMS cells can improve the survival of ischemic skin flap by promoting vascularization, which may be attributed to the increased expression of VEGF and bFGF.

Analogues of uracil nucleosides with intrinsic fluorescence (NIF-analogues): synthesis and photophysical properties

Uridine cannot be utilized as fluorescent probe due to its extremely low quantum yield. For improving the uracil fluorescence characteristics we extended the natural chromophore at the C5 position by coupling substituted aromatic rings directly or via an alkenyl or alkynyl linker to create fluorophores. Extension of the uracil base was achieved by treating 5-I-uridine with the appropriate boronic acid under the Suzuki coupling conditions. Analogues containing an alkynyl linker were obtained from 5-I-uridine and the suitable boronic acid in a Sonogashira coupling reaction. The uracil fluorescent analogues proposed here were designed to satisfy the following requirements: a minimal chemical modification at a position not involved in base-pairing, resulting in relatively long absorption and emission wavelengths and high quantum yield. 5-((4-Methoxy-phenyl)-trans-vinyl)-2'-deoxy-uridine, 6b, was found to be a promising fluorescent probe. Probe 6b exhibits a quantum yield that is 3000-fold larger than that of the natural chromophore (Φ 0.12), maximum emission (478 nm) which is 170 nm red shifted as compared to uridine, and a Stokes shift of 143 nm. In addition, since probe 6b adopts the anti conformation and S sugar puckering favored by B-DNA, it makes a promising nucleoside analogue to be incorporated in an oligonucleotide probe for detection of genetic material.

Synthesis of nonionic ether-backbone analogues of RNA from pseudooligosaccharides

Uracil nucleosides with internucleosidic ether linkage as nonionic analogues of RNA were synthesized by glycosylation of ether-backbone pseudooligosaccharides.

Desulfurization of 2-thiouracil nucleosides: Conformational studies of 4-pyrimidinone nucleosides

4-Pyrimidinone ribofuranoside ( H 2o 4U ) and 4-pyrimidinone 2′-deoxyribofuranoside ( dH 2o 4U ) were synthesized by the oxidative desulfurization of parent 2–thiouracil nucleosides with m-chloroperbenzoic acid. The crystal structures of H 2o 4U and dH 2o 4U and their conformations in solution were determined and compared with corresponding 2-thiouracil and uracil nucleosides. The absence of a large 2-thiocarbonyl/2-carbonyl group in the nucleobase moiety results in C2′- endo puckering of the ribofuranose ring (S conformer) in the crystal structure of H 2o 4U , which is not typical of RNA nucleosides. Interestingly, the hydrogen bonding network in the crystals of dH 2o 4U stabilizes the sugar moiety conformation in the C3′- endo form (N conformer), rarely found in DNA nucleosides. In aqueous solution, dH 2o 4U reveals a similar population of the C2′- endo conformation (65%) to that of 2′-deoxy-2-thiouridine (62%), while the 62% population of the S conformer for H 2o 4U is significantly different from that of the parent 2-thiouridine, for which the N conformer is dominant (71%). Such a difference may be of biological importance, as the desulfurization process of natural tRNA 2-thiouridines may occur under conditions of oxidative stress in the cell and may influence the decoding process.

ChemInform Abstract: Selenoxide Elimination for the Synthesis of Unsaturated Sugar Uracil Nucleosides.

ChemInform Abstract: Selenoxide Elimination for the Synthesis of Unsaturated Sugar Uracil Nucleosides.

ChemInform Abstract: Synthesis and Antiviral Activity of Novel anti-VZV 5-Substituted Uracil Nucleosides with a Cyclopropane Sugar Moiety.

ChemInform Abstract: Synthesis and Antiviral Activity of Novel anti-VZV 5-Substituted Uracil Nucleosides with a Cyclopropane Sugar Moiety.

PCR-based methods for CDA K27Q and A70T genotyping: genotypes and alleles distribution in a central Italy population

Cytidine deaminase (CDA) is a pyrimidine salvage pathway enzyme that catalyzes the hydrolytic deamination of cytidine and deoxycytidine to their corresponding uracil nucleosides. CDA also catalyzes the inactivation of some chemotherapeutic nucleoside analogues such as cytosine arabinoside and gemcitabine. CDA 79A > C (K27Q, rs2072671) and 208G > A (A70T, rs60369023) were found to be associated either with clinical outcomes as well as with pharmacokinetics and toxicity of drugs administered to different subsets of patients. In this paper we reported two PCR-based methods for CDA 79A > C (K27Q) and 208G > A (A70T) genotyping and tested their feasibility using DNA extracted from whole blood as well as from buccal swabs. The aim of this study was also to assess the distribution of genotypic variants in a central Italy population. The allele frequencies were 56.3% (K*) and 43.7% (Q*) for K27Q and 100% (A*) and 0% (T*) for A70T. The genotype frequencies were 32.8% (K*/K*), 46.9% (K*/Q*) and 20.3% (Q*/Q*) for K27Q. The genotype frequencies did not deviate from Hardy-Weinberg equilibrium. The results were compared with those of other reported populations. They showed marked ethnic group differences.

Synthesis of 4,6-dideoxy-3-fluoro-2-keto-β- d-glucopyranosyl analogues of 5-fluorouracil, N6-benzoyl adenine, uracil, thymine, N4-benzoyl cytosine and evaluation of their antitumor activities

The synthesis of the unsaturated 4,6-dideoxy-3-fluoro-2-keto-β- d-glucopyranosyl nucleosides of 5-fluorouracil ( 6a), N 6-benzoyl adenine ( 6b), uracil ( 6c), thymine ( 6d) and N 4-benzoyl cytosine ( 6e), is described. Monoiodination of compounds 1a, b, followed by acetylation, catalytic hydrogenation and finally regioselective 2′- O-deacylation afforded the partially acetylated dideoxynucleoside analogues of 5-fluorouracil ( 5a) and N 6-benzoyl adenine ( 5b), respectively. Direct oxidation of the free hydroxyl group at the 2′-position of 5a, b, with simultaneous elimination reaction of the β-acetoxyl group, afforded the desired unsaturated 4,6-dideoxy-3-fluoro-2-keto-β- d-glucopyranosyl derivatives 6a, b. Compounds 1c– e were used as starting materials for the synthesis of the dideoxy unsaturated carbonyl nucleosides of uracil ( 6c), thymine ( 6d) and N 4-benzoyl cytosine ( 6e). Similarly a protection-selective deprotection sequence followed by oxidation of the free hydroxyl group at the 2′-position of the dideoxy benzoylated analogues 9c– e with simultaneous elimination reaction of the β-benzoyl group, gave the desired nucleosides 6c– e. None of the compounds was inhibitory to a broad spectrum of DNA and RNA viruses at subtoxic concentrations. The 5-fluorouracil derivative 6a was more cytostatic (50% inhibitory concentration ranging between 0.2 and 12 μM) than the other compounds.

Unsaturated dideoxy fluoro-ketopyranosyl nucleosides as new cytostatic agents: A convenient synthesis of 2,6-dideoxy-3-fluoro-4-keto-β- d-glucopyranosyl analogues of uracil, 5-fluorouracil, thymine, N4-benzoyl cytosine and N6-benzoyl adenine

The β-protected nucleosides of uracil ( 2a), 5-fluorouracil ( 2b), thymine ( 2c), N 4-benzoyl cytosine ( 2d) and N 6-benzoyl adenine ( 2e) were synthesized by condensation of the peracetylated 3-deoxy-3-fluoro- d-glucopyranose ( 1) with the corresponding silylated bases. The nucleosides were deacetylated and several subsequent protection and deprotection steps afforded the partially acetylated analogues 6a– e. Selective iodination followed by hydrogenation gave the acetylated dideoxy analogues of uracil ( 8a), 5-fluorouracil ( 8b), thymine ( 8c), N 4-benzoyl cytosine ( 8d) and N 6-benzoyl adenine ( 8e), respectively. Finally, direct oxidation of the free hydroxyl group at the 4′-position of 8a– e, and simultaneous elimination reaction of the β-acetoxyl group, afforded the desired unsaturated 2,6-dideoxy-3-fluoro-4-keto-β- d-glucopyranosyl derivatives 9a– e. The new analogues were evaluated for antiviral and cytostatic activity. Compounds 9a– e were not active against a broad panel of DNA and RNA viruses at subtoxic concentrations. However, they were markedly cytostatic against a variety of tumor cell lines. The compounds should be regarded as potential new lead compounds to be further investigated for anticancer therapy.

Synthesis and Biological Evaluation of 3,3-Difluoropyridine-2,4(1H,3H)-dione and 3-Deaza-3-fluorouracil Base and Nucleoside Derivatives

New 3-deaza-3-halouracil nucleosides including 3-deaza-3-fluorouridine and its 2'-deoxy and arabino analogues have been prepared by fluorination of protected precursors. The resulting 3,3-difluoropyridine-2,4(1H,3H)-dione derivatives underwent palladium-catalyzed hydrogenolysis of one C-F bond at atmospheric pressure, and deprotection gave the 3-deaza-3-fluorouracil compounds. Selective reaction of a stabilized Wittig reagent at C4 of the 3,3-difluoro-2,4-dione intermediates gave exocyclic alkenes that underwent hydrogenation accompanied by spontaneous elimination of hydrogen fluoride. Ammonolysis of the exocyclic carbethoxymethyl substituent and ester protecting groups gave 4-(carboxamidomethyl)-3-deaza-3-fluorouridine and its analogues. Grignard additions at C4 of the ribo and 2'-deoxy 3,3-difluoro-2,4-dione intermediates followed by deprotection gave the 3-deaza-3,3-difluoro-4-hydroxy-4-(substituted)uracil nucleosides. The cytostatic activity of 3-fluoro-3-deazauridine (CC(50) = 4.4-9.6 microM) in three cancer cell lines paralleled that of 3-deazauridine, whereas no significant inhibitory activity was observed with a variety of virus-infected cell cultures.

Candidate New Species ofKobuvirusin Porcine Hosts

Candidate New Species of<i>Kobuvirus</i>in Porcine Hosts

Synthesis of Enantiomerically Pure (S)-Methanocarbaribo Uracil Nucleoside Derivatives for Use as Antiviral Agents and P2Y Receptor Ligands

We have developed an approach toward enantiomerically pure (S)-methanocarba ribonucleosides based on several functional group transformations on a sensitive bicyclo[3.1.0]hexane system. D-ribose was transformed into methanocarba alcohol 3 followed by conversion of the OH group to a nitrile with inversion of configuration at C4. The nitrile group was subsequently reduced in two stages to the 5'-hydroxymethyl group. An ester group appended to a tertiary carbon (C1) was transformed to an amino group as a nucleobase precursor.

Racemic Synthesis and Antiviral Evaluation of 4′(α)-Hydroxymethyl and 6′(α)-Methyl Substituted Apiosyl Nucleosides

This article reports the novel synthesis of substituted apiosyl nucleosides. The key apiosyl intermediate 9 was constructed by sequential ozonolysis, reductions, and acetylation from the ester derivative 6. The nucleosides of uracil, thymine, cytosine, and adenine were synthesized using the glycosyl condensation procedure (silyated base and TMSOTf). The antiviral activities of the synthesized compounds against the HIV-1, HSV-1, HSV-2, and HCMV viruses were evaluated. The adenine derivative 26 showed weak anti-HIV activity (EC50 = 10.1 μg/ml) without exhibiting any cytotoxicity up to a concentration of 100 μM.

An efficient synthesis of 3-fluoro-5-thio-xylofuranosyl nucleosides of thymine, uracil, and 5-fluorouracil as potential antitumor or/and antiviral agents

1,2:5,6-Di- O-isopropylidene-α- d-glucofuranose by the sequence of mild oxidation, reduction, fluorination, periodate oxidation, borohydride reduction, and sulfonylation gave 3-deoxy-3-fluoro-1,2- O-isopropylidene-5- O- p-toluenesulfonyl-α- d-xylofuranose ( 5). Tosylate 5 was converted to thioacetate derivative 6, which after acetolysis gave 1,2-di- O-acetyl-5- S-acetyl-3-deoxy-3-fluoro-5-thio- d-xylofuranose ( 7). Condensation of 7 with silylated thymine, uracil, and 5-fluorouracil afforded nucleosides 1-(5- S-acetyl-3-deoxy-3-fluoro-5-thio-β- d-xylofuranosyl) thymine ( 8), 1-(5- S-acetyl-3-deoxy-3-fluoro-5-thio-β- d-xylofuranosyl) uracil ( 9), and 1-(5- S-acetyl-3-deoxy-3-fluoro-5-thio-β- d-xylofuranosyl) 5-fluorouracil ( 10). Compounds 8, 9, and 10 are biologically active against rotavirus infection and the growth of tumor cells.

Cysteinyl-Leukotriene Receptors and Cellular Signals

Cysteinyl-leukotrienes (cysteinyl-LTs) exert a range of proinflammatory effects, such as constriction of airways and vascular smooth muscle, increase of endothelial cell permeability leading to plasma exudation and edema, and enhanced mucus secretion. They have proved to be important mediators in asthma, allergic rhinitis, and other inflammatory conditions, including cardiovascular diseases, cancer, atopic dermatitis, and urticaria. The classification into subtypes of the cysteinyl-LT receptors (CysLTRs) was based initially on binding and functional data, obtained using the natural agonists and a wide range of antagonists. CysLTRs have proved remarkably resistant to cloning. However, in 1999 and 2000, the CysLT1R and CysLT2R were successfully cloned and both shown to be members of the G-protein coupled receptors (GPCRs) superfamily. Molecular cloning has confirmed most of the previous pharmacological characterization and identified distinct expression patterns only partially overlapping. Recombinant CysLTRs couple to the Gq/11 pathway that modulates inositol phospholipids hydrolysis and calcium mobilization, whereas in native systems, they often activate a pertussis toxin-insensitive Gi/o-protein, or are coupled promiscuously to both G-proteins. Interestingly, recent data provide evidence for the existence of an additional receptor subtype that seems to respond to both cysteinyl-LTs and uracil nucleosides, and of an intracellular pool of CysLTRs that may have roles different from those of plasma membrane receptors. Finally, a cross-talk between the cysteinyl-LT and the purine systems is being delineated. This review will summarize recent data derived from studies on the molecular and cellular pharmacology of CysLTRs.

Rapid microwave-assisted fluorination yielding novel 5′-deoxy-5′-fluorouridine derivatives

The preparation of 18F-labeled ligands for positron emission tomography (PET) and the subsequent imaging have to be completed within a half-life of the neutron-deficient isotope ( 18F = 110 min). In this paper, we report a rapid fluorination approach to obtain 5′-deoxy-5′-fluoro-substituted uracil nucleoside analogues. Nucleophilic substitution at the 5′-position of the nucleosides was achieved within 45 min providing excellent yields of 75–92% by application of microwaves.

Nucleic Acid Related Compounds. Part 129. Hydrothermal Deamidation of 4‐N‐Acylcytosine Nucleoside Derivatives: Efficient Synthesis of Uracil Nucleoside Esters.

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Hydrothermal Deamidation of 4-N-Acylcytosine Nucleoside Derivatives: Efficient Synthesis of Uracil Nucleoside Esters

[reaction: see text] N,O-Peracylated cytidine and 2'-deoxycytidine derivatives in superheated water/DME solutions (oil bath at 125 degrees C) undergo hydrolytic deamidation (and/or N-deacylation). Acylated starting materials derived from arylcarboxylic acids give the corresponding uridine esters cleanly, and such derivatives crystallize selectively from the cooled reaction mixtures in high yields.