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Journal of Medicinal Chemistry Nov 1993In searching for derivatives of pyrazofurin that could display antiviral properties by means that do not require C-5' phosphorylation, 5'-deoxypyrazofurin (3) has been...
In searching for derivatives of pyrazofurin that could display antiviral properties by means that do not require C-5' phosphorylation, 5'-deoxypyrazofurin (3) has been synthesized in six steps from methyl5-deoxy-2,3-O-isopropylidene-beta-D-ribofuranoside (4). Compound 3 was evaluated for antiviral activity against a large number of viruses including herpes-, pox-, myxo-, toga-, arena-, rhabdo-, picorna-,reo-, and retroviruses. Compound 3 proved active against respiratory syncytial virus (in HeLa cells), vaccinia virus (in embryonic skin-muscle fibroblast cells), vesicular stomatitis virus (in HeLa cells), and influenza A virus (in Madin-Darby canine kidney cells) at concentrations (ranging from 4 to 20 micrograms/mL) that were nontoxic to the confluent host cell cultures.
Topics: Animals; Antiviral Agents; Cell Line; Deoxyribonucleosides; Dogs; Embryo, Mammalian; HeLa Cells; Humans; Influenza A virus; Kidney; Respiratory Syncytial Virus, Human; Vaccinia virus; Vesicular stomatitis Indiana virus; Viruses
PubMed: 8246242
DOI: 10.1021/jm00075a030 -
Journal of Computational Chemistry Dec 2012Utilizing the recently developed ONIOM-ccCA methodology, the proton affinities (PAs) of small biomolecules (∼15 nonhydrogen atoms) were determined. The ONIOM-ccCA...
Utilizing the recently developed ONIOM-ccCA methodology, the proton affinities (PAs) of small biomolecules (∼15 nonhydrogen atoms) were determined. The ONIOM-ccCA method was used to predict the PAs of eight amine-containing molecules and these predictions were then compared with experiment. In these comparisons, a protocol for the determination of the model system size was established, and the low level method and basis set for the real system component of ONIOM-ccCA were considered. Several possible density functionals were investigated for description of the real system (low layer), including B3LYP, B97-1, B97-2, B98, BMK, M06, and M06-2X. The resulting proton affinities were compared both to experiment and to theoretical values that were calculated using the correlation consistent Composite Approach (ccCA). The impact of the choice of augmented correlation consistent basis sets in the ONIOM-ccCA low level calculation was also examined, and PAs calculated with augmented and non-augmented basis sets were compared to those extrapolated to the complete basis set (CBS) limit. ONIOM(ccCA:B3LYP/aug-cc-pVDZ) was then applied to deoxyribonucleosides to determine the PAs at possible sites of protonation.
Topics: Deoxyribonucleosides; Protons; Quantum Theory
PubMed: 22941806
DOI: 10.1002/jcc.23102 -
Nucleosides, Nucleotides & Nucleic Acids 2002A rapid and high yielding method for the synthesis of precursors of synthons for DNA synthesis, N-protected 2'-deoxyribonucleosides is described, which occur under mild...
A rapid and high yielding method for the synthesis of precursors of synthons for DNA synthesis, N-protected 2'-deoxyribonucleosides is described, which occur under mild conditions using microwave irradiation. The desired material, N-protected nucleosides, was obtained in 93-96% yield in few minutes. The final products were then characterized by 1H-NMR and MALDI-TOF and compared with the standard samples. The method is amenable to small to moderate scale of synthesis.
Topics: Deoxycytidine; Deoxyribonucleosides; Hydrolysis; Kinetics; Magnetic Resonance Spectroscopy; Microwaves; Models, Chemical; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
PubMed: 12182351
DOI: 10.1081/NCN-120006833 -
Nucleic Acids Research Feb 2003The deamination of nucleobases in DNA occurs by a variety of mechanisms and results in the formation of hypoxanthine from adenine, uracil from cytosine, and xanthine and...
The deamination of nucleobases in DNA occurs by a variety of mechanisms and results in the formation of hypoxanthine from adenine, uracil from cytosine, and xanthine and oxanine from guanine. 2'-Deoxyxanthosine (dX) has been assumed to be an unstable lesion in cells, yet no study has been performed under biological conditions. We now report that dX is a relatively stable lesion at pH 7, 37 degrees C and 110 mM ionic strength, with a half-life (t(1/2)) of 2.4 years in double-stranded DNA. The stability of dX as a 2'-deoxynucleoside (t(1/2) = 3.7 min at pH 2; 1104 h at pH 6) was increased substantially upon incorporation into a single-stranded oligodeoxynucleotide, in which the half-life of dX at different pH values was found to range from 7.7 h at pH 2 to 17 700 h at pH 7. Incorporation of dX into a double-stranded oligodeoxynucleotide resulted in a statistically insignificant increase in the half-life to 20 900 h at pH 7. Data for the pH dependence of the stability of dX in single-stranded DNA were used to determine the rate constants for the acid-catalyzed (2.6 x 10(-5) x s(-1)) and pH-independent (1.4 x 10(-8) x s(-1)) depurination reactions for dX as well as the dissociation constant for the N7 position of dX (6.1 x 10(-4) M). We conclude that dX is a relatively stable lesion that could play a role in deamination-induced mutagenesis.
Topics: Amination; DNA; Deoxyribonucleosides; Half-Life; Hydrogen-Ion Concentration; Kinetics; Models, Chemical; Oligodeoxyribonucleotides
PubMed: 12560502
DOI: 10.1093/nar/gkg177 -
The Journal of Organic Chemistry Feb 2008Polycyclic aromatic hydrocarbons (PAHs) are major environmental carcinogens produced in the combustion of fossil fuels, tobacco, and other organic matter. Current...
Polycyclic aromatic hydrocarbons (PAHs) are major environmental carcinogens produced in the combustion of fossil fuels, tobacco, and other organic matter. Current evidence indicates that PAHs are transformed enzymatically to active metabolites that react with DNA to form adducts that result in mutations. Three activation pathways have been proposed: the diol epoxide path, the radical-cation path, and the quinone path. The latter involves aldo-keto reductase mediated oxidation of PAH dihydrodiol metabolites to catechols that enter into redox cycles with quinones. This results in generation of reactive oxygen species (ROS) that attack DNA, and the PAH quinones also react with DNA to form adducts. Several strategies for synthesis of the stable adducts formed by the o-quinone metabolites of carcinogenic PAHs with 2'-deoxyribonucleosides were investigated and compared. The PAH quinones studied were benz[a]anthracene-3,4-dione and its 7-methyl- and 7,12-dimethyl- derivatives. The parent PAHs represent a range of carcinogenicity from inactive to highly potent. Two synthetic methods were devised that differ in the catalyst employed, Pd(OAc)(2) or CuI. The Pd-mediated method involved coupling a protected amino-catechol PAH derivative with a halo-2'-deoxyribonucleoside. The copper-mediated method entailed reaction of a halo-PAH catechol derivative with a 2'-deoxyribonucleoside. Adducts of benz[a]anthracene-3,4-dione (and its 7-methyl- and 7,12-dimethyl- derivatives) with 2'-deoxyadenosine and 2'-deoxyguanosine were prepared by these methods. Availability of adducts of these types through synthesis makes possible for the first time biological studies to determine the role of these adducts in tumorigenesis. The copper-mediated method offers advantages of economy, adaptability to large-scale preparation, utility for synthesis of (13)C- or (15)N-labeled analogues, and nonformation of bis-adducts as secondary products.
Topics: Amination; Benzo(a)pyrene; Carcinogens; Catechols; Copper; Deoxyribonucleosides; Halogenation; Isomerism; Molecular Structure; Palladium; Polycyclic Aromatic Hydrocarbons; Quinones
PubMed: 18181642
DOI: 10.1021/jo701667u -
International Journal of Molecular... Mar 2023Nucleoside analogues are important compounds for the treatment of viral infections or cancers. While (chemo-)enzymatic synthesis is a valuable alternative to traditional...
Nucleoside analogues are important compounds for the treatment of viral infections or cancers. While (chemo-)enzymatic synthesis is a valuable alternative to traditional chemical methods, the feasibility of such processes is lowered by the high production cost of the biocatalyst. As continuous enzyme membrane reactors (EMR) allow the use of biocatalysts until their full inactivation, they offer a valuable alternative to batch enzymatic reactions with freely dissolved enzymes. In EMRs, the enzymes are retained in the reactor by a suitable membrane. Immobilization on carrier materials, and the associated losses in enzyme activity, can thus be avoided. Therefore, we validated the applicability of EMRs for the synthesis of natural and dihalogenated nucleosides, using one-pot transglycosylation reactions. Over a period of 55 days, 2'-deoxyadenosine was produced continuously, with a product yield >90%. The dihalogenated nucleoside analogues 2,6-dichloropurine-2'-deoxyribonucleoside and 6-chloro-2-fluoro-2'-deoxyribonucleoside were also produced, with high conversion, but for shorter operation times, of 14 and 5.5 days, respectively. The EMR performed with specific productivities comparable to batch reactions. However, in the EMR, 220, 40, and 9 times more product per enzymatic unit was produced, for 2'-deoxyadenosine, 2,6-dichloropurine-2'-deoxyribonucleoside, and 6-chloro-2-fluoro-2'-deoxyribonucleoside, respectively. The application of the EMR using freely dissolved enzymes, facilitates a continuous process with integrated biocatalyst separation, which reduces the overall cost of the biocatalyst and enhances the downstream processing of nucleoside production.
Topics: Nucleosides; Pentosyltransferases; Enzymes, Immobilized; Biocatalysis; Deoxyribonucleosides; Purine-Nucleoside Phosphorylase
PubMed: 37047056
DOI: 10.3390/ijms24076081 -
Antibiotics and Chemotherapy 1980The deoxyribonucleoside triphosphates (dNTPs) are produced via reduction of the corresponding nucleoside diphosphates and subsequent phosphorylation. The reduction step... (Review)
Review
The deoxyribonucleoside triphosphates (dNTPs) are produced via reduction of the corresponding nucleoside diphosphates and subsequent phosphorylation. The reduction step is catalyzed by the enzyme ribonucleoside diphosphate reductase, an enzyme which is induced in S phase cells. The activity and specificity of this enzyme is controlled by dNTPs and ATP, and this feedback mechanism provides a stringent control of the concentrations of the dNTPs themselves. The pools of the dNTPs vary during the cell cycle and are largest is S phase cells. Moreover, in S phase cells, the difference between the largest pool (dCTP) and the smallest pool (dGTP), is about 20-fold. Also, the pools are compartmentalized into cytoplasmic and nuclear pools, and this compartmentalization is most pronounced in S phase cells. In such cells, the total nuclear concentration of dNTPs is about micronM. Mainly by use of virus-infected cells, results were obtained which indicate a direct involvement of a deoxycytidine nucleotide in the regulation of DNA synthesis.
Topics: Animals; Cell Cycle; Cell Line; DNA; DNA Replication; Deoxyribonucleosides; Deoxyribonucleotides; Enzyme Induction; Herpesviridae Infections; Mammals; Neoplasms; Ribonucleotide Reductases; Simplexvirus
PubMed: 6251748
DOI: 10.1159/000386063 -
Nucleic Acids Research Jul 1992We have investigated the conformations of the hexadeoxyribonucleotide, L-d(CGCGCG) composed of L-deoxyribose, the mirror image molecule of natural D-deoxyribose. In this...
We have investigated the conformations of the hexadeoxyribonucleotide, L-d(CGCGCG) composed of L-deoxyribose, the mirror image molecule of natural D-deoxyribose. In this paper, we report the synthesis of four L-deoxynucleosides and the L-oligonucleotide-ethidium bromide interactions. The L-deoxyribose synthon 9 was synthesized from L-arabinose with an over all yield of 28.5% via the Barton-McCombie reaction. The L-deoxynucleosides were obtained by a glycosylation of appropriate nucleobase derivatives with the 1-chloro sugar 9. After derivatization to nucleoside phosphoramidites, L-deoxycytidine and L-deoxyguanosine were incorporated into a hexadeoxynucleotide, L-d(CGCGCG) by a solid-phase beta-cyanoethylphosphoramidite method. This L-hexanucleotide was resistant to digestion with nuclease P1. The conformations of L-d(CGCGCG) were an exact mirror image of that of the corresponding natural one as described previously, and the conformations of the L-d(CGCGCG)-ethidium bromide complex were also the mirror images of those of the D-d(CGCGCG)-ethidium bromide complex under both low and high salt conditions. These results suggest that ethidium bromide prefers not a right-handed helical sense, but the base-base stacking geometry of the B-form rather than that of the Z-form. Thus, L-DNA would be a useful tool for studying DNA-drug interactions.
Topics: Chromatography, High Pressure Liquid; Deoxyribonucleosides; Nucleic Acid Conformation; Oligodeoxyribonucleotides
PubMed: 1630904
DOI: 10.1093/nar/20.13.3325 -
Nucleic Acids Symposium Series 1987Regiospecific chemical methodologies have been developed for the incorporation of deuterium regio and stereospecifically in all four naturally occurring... (Comparative Study)
Comparative Study
Regiospecific chemical methodologies have been developed for the incorporation of deuterium regio and stereospecifically in all four naturally occurring 2'-deoxynucleosides.
Topics: Deoxyribonucleosides; Deuterium; Isotope Labeling; Stereoisomerism; Structure-Activity Relationship
PubMed: 3697131
DOI: No ID Found -
Biochemistry Dec 1999Deoxynucleoside kinases catalyze the 5'-phosphorylation of 2'-deoxyribonucleosides with nucleoside triphosphates as phosphate donors. One of the cellular kinases,...
Deoxynucleoside kinases catalyze the 5'-phosphorylation of 2'-deoxyribonucleosides with nucleoside triphosphates as phosphate donors. One of the cellular kinases, deoxycytidine kinase (dCK), has been shown to phosphorylate several L-nucleosides that are efficient antiviral agents. In this study we investigated the potentials of stereoisomers of the natural deoxyribonucleoside to serve as substrates for the recombinant cellular deoxynucleoside kinases. The cytosolic thymidine kinase exhibited a strict selectivity and phosphorylated only beta-D-Thd, while the mitochondrial thymidine kinase (TK2) and deoxyguanosine kinase (dGK) as well as dCK all had broad substrate specificities. TK2 phosphorylated Thd and dCyd stereoisomers in the order: beta-D- > or = beta-L- >> alpha-D- > or = alpha-L-isomer. dCK activated both enantiomers of beta-dCyd, beta-dGuo, and beta-dAdo with similar efficiencies, and alpha-D-dCyd also served as a substrate. dGK phosphorylated the beta-dGuo enantiomers with no preference for the ribose configuration; alpha-L-dGuo was also phosphorylated, and beta-L-dAdo and beta-L-dCyd were substrates but showed reduced efficiencies. The anomers of the 2',3'-dideoxy-D-nucleosides (ddNs) were tested, and TK2 and dCK retained their low selectivities. Unexpectedly, alpha-dideoxycytidine (ddC) was a 3-fold better substrate for dCK than beta-ddC. Similarly, alpha-dideoxythymidine (ddT) was a better substrate for TK2 than beta-ddT. dGK did not accept any D-ddNs. Thus, TK2, dCK, and dGK, similar to herpes simplex virus type 1 thymidine kinase (HSV-1 TK), showed relaxed stereoselectivities, and these results substantiate the functional similarities within this enzyme family. Docking simulations with the Thd isomers and the active site of HSV-1 TK showed that the viral enzyme may in some respects serve as a model for studying the substrate specificities of the cellular enzymes.
Topics: Binding Sites; Computer Simulation; Deoxyribonucleosides; Herpesvirus 1, Human; Humans; Kinetics; Models, Molecular; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor); Stereoisomerism; Substrate Specificity; Thymidine; Thymidine Kinase
PubMed: 10606535
DOI: 10.1021/bi9908843