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Biochimica Et Biophysica Acta Dec 2007Cytotoxic deoxynucleoside analogues are widely used in the treatment of haematological malignancies and solid tumours. Their metabolism and mechanisms of action are... (Review)
Review
Cytotoxic deoxynucleoside analogues are widely used in the treatment of haematological malignancies and solid tumours. Their metabolism and mechanisms of action are relatively well known, but with ongoing technological development, a continuous flow of scientific data is constantly adding new knowledge to this field. Thus, what was already a well-developed area some years ago has continued its expansion and become a better understood part of medical sciences. In order to keep abreast of the latest advances on cellular and clinical resistance to deoxynucleoside analogues, we have reviewed the recent literature and provide here an update on the subject. We have particularly focused on changes in gene products involved in the metabolic pathway of these drugs, such as membrane transporters, kinases, deaminases and 5'-nucleotidases. We also gave an overview on the chemical and biological development of modified deoxynucleoside analogues such as conjugates and pronucleotides.
Topics: 5'-Nucleotidase; Antineoplastic Agents; Deoxyribonucleosides; Drug Resistance, Neoplasm; Humans; Models, Biological; Nucleoside Deaminases; Nucleoside Transport Proteins; Phosphotransferases (Alcohol Group Acceptor); Ribonucleotide Reductases
PubMed: 17881132
DOI: 10.1016/j.bbcan.2007.07.004 -
EBioMedicine Sep 2019
Topics: Animals; DNA, Mitochondrial; Deoxyribonucleosides; Mice; Mitochondria; Thymidine Kinase
PubMed: 31402231
DOI: 10.1016/j.ebiom.2019.08.005 -
Physical Chemistry Chemical Physics :... Nov 2012Relaxed force constants (RFC) and vibrational root-mean-square (VRMS) deviations are used for comparative characterization of mechanical properties of canonical...
Relaxed force constants (RFC) and vibrational root-mean-square (VRMS) deviations are used for comparative characterization of mechanical properties of canonical 2'-deoxyribonucleosides (2DRs) and 1,2-dideoxyribose molecule, their model sugar residue. It has been shown that RFC and VRMS should be preferred over traditional force constants when one needs to obtain the quantitative measure of the 'collective' parameter flexibility (furanose sugar pseudorotation phase P in particular) and compare it with classical torsion angles (β, γ, ε, χ). It has been found that torsions ε and β determining the 2DRs backbone hydroxyl orientations are as soft as the pseudorotation phase P with RFC values within 1-10 kcal mol(-1) rad(-2) depending on conformation. Torsion γ is the most rigid one with RFC 15-30 kcal mol(-1) rad(-2), while the glycosidic torsion χ is characterized by intermediate values of RFC (typically 5-10 kcal mol(-1) rad(-2)) and its RFC changes by 10 times, depending on the furanose sugar conformation (K(χ)≈ 3 kcal mol(-1) rad(-2) in B- vs. K(χ)≈ 21 kcal mol(-1) rad(-2) in A-DNA-like conformation of 2'-deoxycytidine). Quantum zero-point motion of the nuclei makes the dominant contribution to VRMS deviations of molecules structural parameters: 9-22° for β, ε and P, 5-7° for γ and χ at the temperature of 0 K, and 15-38° for β, ε and P, 9-26° for γ and χ at the room temperature (298.15 K). Obtained results can be used in constructing simple dynamical models of the DNA fragments.
Topics: Deoxyribonucleosides; Deoxyribose; Nucleic Acid Conformation; Quantum Theory; Vibration
PubMed: 23073508
DOI: 10.1039/c2cp43120c -
Basic Life Sciences 1985Treatment of Chinese hamster V79 cells with dThd, dCyd, or dThd plus dCyd increased MNNG-induced AGr-, TGr-, and Ouar-mutant frequencies but did not significantly... (Review)
Review
Treatment of Chinese hamster V79 cells with dThd, dCyd, or dThd plus dCyd increased MNNG-induced AGr-, TGr-, and Ouar-mutant frequencies but did not significantly increase background mutant frequencies. All the AGr colonies that were isolated possessed phenotypes characteristic of HGPRT-deficient mutants, and the deoxyribonucleosides did not selectively affect the growth of the mutants, nor the selecting efficiency of AG, and did not significantly enhance background mutagenesis. These data show that both dThd and dCyd facilitated MNNG-induced mutagenesis. This facilitation was maximal when cells were exposed to the deoxyribonucleosides throughout the first doubling time (24 h) after treatment with MNNG and for 4 more doubling times prior to mutant selection with AG. This indicates that one round of DNA replication was sufficient for mispairing of methylated bases in the DNA with the C and T provided by the deoxyribonucleosides, and that 4-6 doublings prior to mutant selection with AG were necessary to deplete pre-existing hypoxanthine: guanine phosphoribosyl transferase in newly mutated cells. The dCyd facilitated mutagenesis by FdUrd, which was not mutagenic without dCyd, indicating that increased dCTP:dTTP ratios were mutagenic. Treatment with FdUrd plus dCyd also induced FdUrdr cells, suggesting that inhibition of dCyd utilization may prevent the development of FdUrd-resistance in cancer chemotherapy. Although dCyd and dThd facilitated mutagenesis in cells treated with monofunctional alkylating agents that methylate DNA oxygens, facilitation of mutagenesis did not occur in cells treated with BCNU, which cross links DNA, nor with benzo(a)pyrene and aflatoxin B1, which are frame shift mutagens, nor with MMS, which produces barely detectable levels of O-methylation in DNA. Virtually non toxic concentrations of dThd potentiated the cytotoxicity of MNNG more than 10-fold but that of MMS was potentiated only about 2-fold showing that O-alkylation of DNA was associated not only with the facilitation of mutagenesis but also with the potentiation of cytotoxicity. The potentiation of MNNG-induced cytotoxicity was maximal in V79 and L1210 cells after only 2 h treatment with dThd, showing that not even one round of DNA replication was necessary for this potentiation. Moreover, dCyd abolished the potentiation, and, at equitoxic concentrations, MNNG induced higher mutant frequencies than did MMS. These data show that the mechanisms by which methylating agents plus dThd induce mutagenesis are fundamentally different from their mechanisms of cytotoxicity.(ABSTRACT TRUNCATED AT 400 WORDS)
Topics: Alkylating Agents; Animals; Azaguanine; Cell Line; Cell Survival; Cricetinae; DNA; Deoxyadenosines; Deoxycytidine; Deoxycytosine Nucleotides; Deoxyguanosine; Deoxyribonucleosides; Drug Resistance; Drug Synergism; Floxuridine; Leukemia L1210; Lung; Methylation; Methylnitronitrosoguanidine; Mice; Mutagens; Mutation; Thymidine; Thymidylate Synthase; Thymine Nucleotides
PubMed: 3158302
DOI: 10.1007/978-1-4613-2449-2_19 -
Bioorganic & Medicinal Chemistry Feb 2019We report herein the synthesis and evaluation of a series of β-d-2'-deoxy-2'-α-chloro-2'-β-fluoro and β-d-2'-deoxy-2'-α-bromo-2'-β-fluoro nucleosides along with...
We report herein the synthesis and evaluation of a series of β-d-2'-deoxy-2'-α-chloro-2'-β-fluoro and β-d-2'-deoxy-2'-α-bromo-2'-β-fluoro nucleosides along with their corresponding phosphoramidate prodrugs. Key intermediates, lactols 11 and 12, were obtained by a diastereoselective fluorination of protected 2-deoxy-2-chloro/bromo-ribonolactones 7 and 8. All synthesized nucleosides and prodrugs were evaluated with a hepatitis C virus (HCV) subgenomic replicon system.
Topics: Animals; Antiviral Agents; Cell Line, Tumor; Chlorocebus aethiops; Deoxyribonucleosides; Hepacivirus; Humans; Prodrugs; Stereoisomerism; Vero Cells
PubMed: 30655167
DOI: 10.1016/j.bmc.2019.01.005 -
Chemical Research in Toxicology 1995A new type of 1-nitropyrene--DNA adduct via addition--elimination reaction was synthesized. Treatment of fluorinated 1-nitropyrene with 3'- and 5'-O-protected...
A new type of 1-nitropyrene--DNA adduct via addition--elimination reaction was synthesized. Treatment of fluorinated 1-nitropyrene with 3'- and 5'-O-protected 2'-deoxyribonucleoside in dimethyl sulfoxide at 140 degrees C afforded N-(1-nitropyren-6-yl or 8-yl)-2'-deoxyribonucleoside. These DNA adducts resulted from addition of the exocyclic amino group of deoxynucleosides to the fluorinated carbon of the fluoro-1-nitropyrene following elimination of fluoride anion. This is the first report that describes the 1-nitropyrene-DNA adducts in which aromatic ring moiety of 1-nitropyrene is covalently linked to the exocyclic amino group of the deoxyribonucleoside. From our findings, we suggest that the addition-elimination reaction may be responsible for the formation mechanism of the putative 1-nitropyrene--DNA adducts in vivo.
Topics: DNA Adducts; Deoxyribonucleosides; Magnetic Resonance Spectroscopy; Mutagens; Pyrenes; Spectrum Analysis
PubMed: 7548752
DOI: 10.1021/tx00047a009 -
Organic & Biomolecular Chemistry Aug 20182'-Deoxyribonucleoside triphosphates (dNTPs) containing 5-(hydroxymethyl)cytosine (5hmC) protected with photocleavable groups (2-nitrobenzyl or 6-nitropiperonyl) were...
2'-Deoxyribonucleoside triphosphates (dNTPs) containing 5-(hydroxymethyl)cytosine (5hmC) protected with photocleavable groups (2-nitrobenzyl or 6-nitropiperonyl) were prepared and studied as substrates for the enzymatic synthesis of oligonucleotides and DNA containing a photocaged epigenetic 5hmC base. DNA probes containing photocaged or free 5hmC in the recognition sequence of restriction endonucleases were prepared and used for the study of the photorelease of caged DNA by UV or visible light at different wavelengths. The nitrobenzyl-protected dNTP was a slightly better substrate for DNA polymerases in primer extension or PCR, whereas the nitropiperonyl-protected nucleotide underwent slightly faster photorelease at 400 nm. However, both photocaged building blocks can be used in polymerase synthesis and the photorelease of 5hmC in DNA.
Topics: 5-Methylcytosine; DNA; Deoxyribonucleosides; Light; Photochemical Processes; Polyphosphates; Ultraviolet Rays
PubMed: 29905748
DOI: 10.1039/c8ob01106k -
Journal of Agricultural and Food... Jul 19992'-Deoxyribonucleosides, ribonucleosides, nucleobases, deoxyribose, and ribose were oxidized with Fenton's reagent. Malonaldehyde (MA) formed was derivatized with...
2'-Deoxyribonucleosides, ribonucleosides, nucleobases, deoxyribose, and ribose were oxidized with Fenton's reagent. Malonaldehyde (MA) formed was derivatized with N-methylhydrazine to N-methylpyrazole, and acetaldehyde formed was derivatized with cysteamine to 2-methylthiazolidine. The resulting nitrogen-containing derivatives were quantitatively analyzed using gas chromatography with a nitrogen-phosphorus detector. MA and acetaldehyde were found in 2-deoxy-D-ribose and 2'-deoxyribonucleosides but not in ribonucleosides, nucleobases, and D-ribose. Amounts of MA formed from four deoxynucleosides were in the following order: 2'-deoxyguanosine > 2'-deoxycytidine > 2'-deoxyadenosine > or = thymidine. Amounts of acetaldehyde formed from four deoxynucleosides were in the following order: 2'-deoxycytidine > thymidine > 2'-deoxyadenosine > or = 2'-deoxyguanosine. The results suggest that the formation of MA and acetaldehyde requires a deoxy group on carbon 2' of a ribose moiety.
Topics: Acetaldehyde; Chromatography, Gas; Deoxyribonucleosides; Malondialdehyde; Oxidation-Reduction
PubMed: 10552565
DOI: 10.1021/jf990109u -
Current Protocols in Nucleic Acid... Mar 20204-Cyanoindole-2'-deoxyribonucleoside (4CIN) is a fluorescent isomorphic nucleoside analogue with superior spectroscopic properties in terms of Stokes shift and quantum...
4-Cyanoindole-2'-deoxyribonucleoside (4CIN) is a fluorescent isomorphic nucleoside analogue with superior spectroscopic properties in terms of Stokes shift and quantum yield in comparison to the widely utilized isomorphic nucleoside analogue, 2-aminopurine-2'-deoxyribonucleoside (2APN). Notably, when inserted into single- or double-stranded DNA, 4CIN experiences substantially less in-strand fluorescence quenching compared to 2APN. Given the utility of these properties for a spectrum of research applications involving oligonucleotides and oligonucleotide-protein interactions (e.g., enzymatic processes, DNA hybridization, DNA damage), we envision that additional reagents based on 4-cyanoindole nucleosides may be widely utilized. This protocol expands on the previously published synthesis of 4CIN to include synthetic routes to both 4-cyanoindole-ribonucleoside (4CINr) and 4-cyanoindole-2'-deoxyribonucleoside-5'-triphosphate (4CIN-TP), as well as a method for the enzymatic incorporation of 4CIN-TP into DNA by a polymerase. These methods are anticipated to further enable the utilization of 4CIN in diverse applications involving DNA and RNA oligonucleotides. © 2020 by John Wiley & Sons, Inc. Basic Protocol 1: Synthesis of 4-cyanoindole-2'-deoxyribonucleoside (4CIN) and 4CIN phosphoramidite 4 Basic Protocol 2: Synthesis of 4-cyanoindole-ribonucleoside (4CINr) Basic Protocol 3: Synthesis of 4-cyanoindole-2'-deoxyribonucleoside-5'-triphosphate (4CIN-TP) Basic Protocol 4: Steady state incorporation kinetics of 2AP-TP and 4CIN-TP by a DNA polymerase.
Topics: Carbon-13 Magnetic Resonance Spectroscopy; Cyanides; DNA; Deoxyribonucleosides; Indoles; Mass Spectrometry; Nucleosides; Proton Magnetic Resonance Spectroscopy
PubMed: 31909864
DOI: 10.1002/cpnc.101 -
Pharmacology & Therapeutics 1984
Review
Topics: Animals; Antimetabolites; DNA; Deoxyadenine Nucleotides; Deoxycytosine Nucleotides; Deoxyguanine Nucleotides; Deoxyribonucleosides; Deoxyribonucleotides; Humans; Kinetics; Liver Neoplasms, Experimental; Models, Biological; Nucleic Acid Synthesis Inhibitors; Ribonucleoside Diphosphate Reductase; Thermodynamics; Thymidylate Synthase; Thymine Nucleotides
PubMed: 6379685
DOI: 10.1016/0163-7258(84)90038-x