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Chemical Research in Toxicology 1996Estrogens can have two roles in the induction of cancer: stimulating proliferation of cells by receptor-mediated processes, and generating electrophilic species that can...
Estrogens can have two roles in the induction of cancer: stimulating proliferation of cells by receptor-mediated processes, and generating electrophilic species that can covalently bind to DNA. The latter role is thought to proceed through catechol estrogen metabolites, which can be oxidized to o-quinones that bind to DNA. Four estrogen-deoxyribonucleoside adducts were synthesized by reaction of estrone 3,4-quinone (E1-3,4-Q), 17 beta-estradiol 3,4-quinone (E2-3,4-Q), or estrone 2,3-quinone (E1-2,3-Q) with deoxyguanosine (dG) or deoxyadenosine (dA) in CH3CO2H/H2O (1:1). Reaction of E1-3,4-Q or E2-3,4-Q with dG produced specifically 7-[4-hydroxyestron-1(alpha, beta)-yl]guanine (4-OHE1-1(alpha, beta)-N7Gua) or 7-[4-hydroxyestradiol-1(alpha, beta)-yl]-guanine (4-OHE2-1(alpha, beta)-N7Gua), respectively, in 40% yield, with loss of deoxyribose. These two quinones did not react with dA, deoxycytidine, or thymidine. When E1-2,3-Q was reacted with dG or dA, N2-(2-hydroxyestron-6-yl)deoxyguanosine (2-OHE1-6-N2dG, 10% yield) and N6-(2-hydroxyestron-6-yl)deoxyadenosine (2-OHE1-6-N6dA, 80% yield), respectively, were formed. These adducts provide insight into the type of DNA damage that can be caused by o-quinones of the catechol estrogens. The estrogen 3,4-quinones are expected to produce depurinating guanine adducts that are lost from DNA, generating apurinic sites, whereas the 2,3-quinones would form stable adducts that remain in DNA, unless repaired. The adducts reported here will be used as references in studies to elucidate the structure of estrogen adducts in biological systems.
Topics: Chromatography, High Pressure Liquid; DNA; DNA Damage; Deoxyribonucleosides; Estrogens, Catechol; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Quinones; Spectrometry, Mass, Fast Atom Bombardment
PubMed: 8828920
DOI: 10.1021/tx960002q -
Chemical Research in Toxicology May 1999Radiation-induced degradation of purine and pyrimidine nucleosides gave rise to carbon-bridged cyclocompounds. Such cyclonucleosides represent a class of tandem lesions...
Synthesis and characterization of oligonucleotides containing 5',8-cyclopurine 2'-deoxyribonucleosides: (5'R)-5',8-cyclo-2'-deoxyadenosine, (5'S)-5',8-cyclo-2'-deoxyguanosine, and (5'R)-5',8-cyclo-2'-deoxyguanosine.
Radiation-induced degradation of purine and pyrimidine nucleosides gave rise to carbon-bridged cyclocompounds. Such cyclonucleosides represent a class of tandem lesions in which modification of both the base and 2-deoxyribose has occurred. A solid-phase synthetic method was designed for the incorporation of both 5'R and 5'S diastereoisomers of 5',8-cyclopurine 2'-deoxyribonucleosides into oligodeoxynucleotides to facilitate the assessment of the biochemical and biophysical features of such lesions. We report the preparation of the phosphoramidite synthons of (5'R)-5', 8-cyclo-2'-deoxyadenosine (2), (5'S)-5',8-cyclo-2'-deoxyguanosine (3), and (5'R)-5',8-cyclo-2'-deoxyguanosine (4). Fully protected compounds 10, 18, and 25 were then inserted into several oligonucleotides by automated procedures. Analysis of modified DNA oligomers 26-31 by electrospray mass spectrometry and enzymatic digestions with exo- and endonucleases confirmed the base compositions and the integrity of free radical-induced tandem lesions 2-4 that were chemically inserted.
Topics: Alkaline Phosphatase; Chromatography, High Pressure Liquid; Deoxyadenosines; Deoxyguanosine; Hydrolysis; Indicators and Reagents; Oligonucleotides; Phosphoric Diester Hydrolases; Single-Strand Specific DNA and RNA Endonucleases; Spectrophotometry, Ultraviolet; Stereoisomerism
PubMed: 10328751
DOI: 10.1021/tx9802668 -
Angewandte Chemie (International Ed. in... Dec 2006
Topics: Deoxyribonucleosides; Indoles; Isoindoles; Molecular Structure; Radiation-Sensitizing Agents; Spectrum Analysis; Zinc
PubMed: 17096445
DOI: 10.1002/anie.200603590 -
Chemical Research in Toxicology Jul 1997Metabolic activation of estradiol leading to the formation of catechol estrogens is believed to be a prerequisite for its genotoxic effects. Previous studies have shown...
Metabolic activation of estradiol leading to the formation of catechol estrogens is believed to be a prerequisite for its genotoxic effects. Previous studies have shown that 3,4-estronequinone (3,4-EQ) can redox-cycle and is capable of inducing exclusively single-strand DNA breaks in MCF-7 breast cancer cells [Nutter et al. (1991) J. Biol. Chem. 226, 16380-16386]. These studies, however, could not provide conclusive evidence about the mechanism of estrogen carcinogenesis. In order to explore this in more detail, we have shown previously that 3,4-EQ can react with adenine under electrochemical reductive conditions to yield an estrogen-nucleic acid adduct [Abul-Hajj et al. (1995) J. Am. Chem. Soc. 117, 6144-6145]. In this paper, we report the synthesis and identification of nine estrogen-nucleic acid adducts obtained from reaction of 3,4-EQ with deoxycytidine, deoxythymidine, deoxyadenosine, and deoxyguanosine. Purification of reaction mixtures using HPLC gave sufficient quantities of reaction products for identification using 1H-NMR and mass spectral determinations. Reaction of 3,4-EQ with dCyd, dThd, dAdo, and dGuo gave the following estrogen-nucleic acid adducts: N4-(4-hydroxyestron-1-yl)deoxycytidine, N4-(4-hydroxyestron-2-yl)deoxycytidine, N3-(4-hydroxyestron-1-yl)thymine, N3-(4-hydroxyestron-1-yl)deoxythymidine, N6-(4-hydroxyestron-1-yl)deoxyadenosine, 8-(4-hydroxyestron-1-yl)adenine, N2-(4-hydroxyestron-1-yl)deoxyguanosine, 8-(4-hydroxyestron-1-yl)guanine, and 8-(4-hydroxyestron-2-yl)guanine. Adduction through the NH2 group of dAdo, dGuo, and dCyd results in formation of chemically stable adducts. On the other hand, adduction at C-8 led to the formation of several depurination adducts identified as 4-OHE1-1-C8-Gua, 4-OHE1-2-C8-Gua, and 4-OHE1-1-C8-Ade.
Topics: Anions; Carcinogens; Chromatography, High Pressure Liquid; Deoxyadenosines; Deoxycytidine; Deoxyguanosine; Deoxyribonucleosides; Estrenes; Free Radicals; Magnetic Resonance Spectroscopy; Thymidine
PubMed: 9250409
DOI: 10.1021/tx970026c -
ACS Chemical Biology Oct 2022Five 2'-deoxyribonucleoside triphosphates (dNTPs) derived from epigenetic pyrimidines (5-methylcytosine, 5-hydroxymethylcytosine, 5-formylcytosine,...
Five 2'-deoxyribonucleoside triphosphates (dNTPs) derived from epigenetic pyrimidines (5-methylcytosine, 5-hydroxymethylcytosine, 5-formylcytosine, 5-hydroxymethyluracil, and 5-formyluracil) were prepared and systematically studied as substrates for nine DNA polymerases in competition with natural dNTPs by primer extension experiments. The incorporation of these substrates was evaluated by a restriction endonucleases cleavage-based assay and by a kinetic study of single nucleotide extension. All of the modified pyrimidine dNTPs were good substrates for the studied DNA polymerases that incorporated a significant percentage of the modified nucleotides into DNA even in the presence of natural nucleotides. 5-Methylcytosine dNTP was an even better substrate for most polymerases than natural dCTP. On the other hand, 5-hydroxymethyl-2'-deoxyuridine triphosphate was not the best substrate for SPO1 DNA polymerase, which naturally synthesizes 5hmU-rich genomes of the SPO1 bacteriophage. The results shed light onto the possibility of gene silencing through recycling and random incorporation of epigenetic nucleotides and into the replication of modified bacteriophage genomes.
Topics: Pyrimidine Nucleotides; 5-Methylcytosine; DNA-Directed DNA Polymerase; Nucleotides; DNA; DNA Restriction Enzymes; Pyrimidines; Deoxyribonucleosides; Epigenesis, Genetic
PubMed: 35679536
DOI: 10.1021/acschembio.2c00342 -
Nucleic Acids Symposium Series 1999Thymidine with the stereoselectively 2H/13C-Labeled sugar moiety, (2'R)(5'S)-[1',2',3',4',5'-(13)C5;2',5'-(2)H2]-thymidine, was synthesized from uniformly 13C-labeled...
Thymidine with the stereoselectively 2H/13C-Labeled sugar moiety, (2'R)(5'S)-[1',2',3',4',5'-(13)C5;2',5'-(2)H2]-thymidine, was synthesized from uniformly 13C-labeled glucose, via the selectively deuterated ribose derivative prepared by the stereo-controlled deuteride transfer reactions. The labeled sugar moiety of the thymidine was then transferred to 2'-deoxyadenosine, 2'-deoxyguanosine, and 2'-deoxyuridine, by the enzymatic transglycosylation reactions by purine and pyrimidine nucleoside phosphorylases, in good yields. Labeled 2'-deoxyuridine was chemically converted to 2'-deoxycytidine. Consequently, all of the 2'-deoxynucleosides prepared by this method has the identically labeled sugar moiety. By using DNA oligomers containing the identically labeled sugar residue for NMR studies, any possible complexity in NMR data analyses expected to be observed for DNA oligomers containing variously labeled nucleosides can be minimized.
Topics: Carbon Isotopes; Deoxyadenosines; Deoxycytidine; Deoxyguanosine; Deoxyribonucleosides; Deoxyuridine; Deuterium; Glucose; Isotope Labeling; Nuclear Magnetic Resonance, Biomolecular; Oligodeoxyribonucleotides; Ribose
PubMed: 10780410
DOI: 10.1093/nass/42.1.123 -
Organic Letters Mar 2005[structure: see text] The first syntheses of the adducts formed in the reactions of o-quinone metabolites of carcinogenic polycyclic aromatic hydrocarbons (BPQ and BAQ)...
[structure: see text] The first syntheses of the adducts formed in the reactions of o-quinone metabolites of carcinogenic polycyclic aromatic hydrocarbons (BPQ and BAQ) at 2'-deoxyadenosine and 2'-deoxyguanosine sites in DNA are reported. These syntheses entail Pd-catalyzed coupling of protected amine derivatives of catechols with suitably protected halopurine analogues of 2'-deoxyribonucleosides.
Topics: Carcinogens; Catalysis; Deoxyribonucleosides; Indicators and Reagents; Molecular Structure; Polycyclic Aromatic Hydrocarbons; Quinones
PubMed: 15760123
DOI: 10.1021/ol0475358 -
Nucleic Acids Symposium Series 1992Highly stereoselective synthesis of (2'R)-[2'-2H]-2'-deoxyribonucleosides (2'R:2'S = > 99:1) were accomplished by treating 2'-bromo-3',5'-O-TPDS-2'-deoxyribonucleosides...
Highly stereoselective synthesis of (2'R)-[2'-2H]-2'-deoxyribonucleosides (2'R:2'S = > 99:1) were accomplished by treating 2'-bromo-3',5'-O-TPDS-2'-deoxyribonucleosides with tributyltin deuteride at lower temperatures such as -60 degrees C in the presence of triethylborane. Moreover, synthesis of some oligodeoxyribonucleosides involving them will be described.
Topics: Boranes; Deoxyribonucleosides; Oligonucleotides; Stereoisomerism; Trialkyltin Compounds
PubMed: 1289834
DOI: No ID Found -
Chemical Research in Toxicology 1991Identification of various deoxyribonucleoside adducts formed in primary cultures of mouse keratinocytes exposed to dibenz[a,j]anthracene (DB[a,j]A) is presented. A... (Comparative Study)
Comparative Study
Identification of various deoxyribonucleoside adducts formed in primary cultures of mouse keratinocytes exposed to dibenz[a,j]anthracene (DB[a,j]A) is presented. A preliminary analysis of the DNA adducts formed from 7-methyldibenz[a,j]anthracene (7MeDB[a,j]A) also is presented. Cultures of keratinocytes obtained from dorsal skins of female SENCAR mice were exposed to 0.5 microgram of tritium-labeled hydrocarbons/mL of medium for 24 h. The total DNA binding was 2.23 +/- 0.54 and 5.28 +/- 0.97 pmol of hydrocarbon/mg of DNA for DB[a,j]A and 7MeDB[a,j]A, respectively. These binding values represented the radioactivity associated with the modified deoxyribonucleosides separated from the normal deoxyribonucleosides on Sephadex LH-20 columns following enzymatic digestion of isolated DNA. Treatment of keratinocytes with DB[a,j]A produced adduct peaks corresponding to marker adducts derived from trans addition of both deoxyguanosine as well as deoxyadenosine residues to the (+) enantiomer of the anti-diol epoxide where the deoxyadenosine adducts were predominant. In addition, DNA adduct peaks corresponding to markers of trans and cis addition, respectively, of deoxyguanosine and deoxyadenosine to the (+)-syn-diol epoxide were also noted in these chromatograms. A major DNA adduct in cells exposed to DB[a,j]A was tentatively identified as resulting from the addition of deoxyadenosine to DB[a,j]A-5,6-oxide. Several other later eluting DNA adduct peaks, not corresponding to any of the marker adducts, were also present in these chromatograms. In comparison, when cells were exposed to the more biologically potent 7-methyl analogue, at least 12 DNA adduct peaks were consistently observed in HPLC chromatograms.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Animals; Benz(a)Anthracenes; Cattle; Cells, Cultured; Chromatography, High Pressure Liquid; DNA; DNA Adducts; Deoxyribonucleosides; Female; Keratinocytes; Mice
PubMed: 1912293
DOI: 10.1021/tx00019a016 -
Journal of Medicinal Chemistry Nov 1980A novel series of cyclophosphamide derivatives of pyrimidine deoxyribonucleosides (6-9) has been synthesized from the corresponding amino nucleosides. Our preliminary...
A novel series of cyclophosphamide derivatives of pyrimidine deoxyribonucleosides (6-9) has been synthesized from the corresponding amino nucleosides. Our preliminary findings have shown that three of these cyclophosphamide nucleoside analogues, 6, 7, and 9, have potent inhibitory effects on the replication of L1210 cells in vitro (ED50 = 1.2-1.5 x 10(-5) M). Since cyclophosphamide (cytoxan) has no cytotoxicity under these conditions, our findings indicate that these novel phosphamide derivatives have unusual biological properties which may include a unique mode of activation.
Topics: Animals; Antineoplastic Agents; Cell Division; Chemical Phenomena; Chemistry; Deoxyribonucleosides; Leukemia L1210; Mice; Phosphoramide Mustards; Pyrimidine Nucleosides
PubMed: 7452673
DOI: 10.1021/jm00185a018