53-95-2Relevant academic research and scientific papers
Comparison of hprt and lacl mutant frequency with DNA adduct formation in N-Hydroxy-2-acetylaminofluorene-treated big blue rats
Chen, Tao,Mittelstaedt, Roberta A.,Aidoo, Anane,Patrice Hamilton,Beland, Frederick A.,Casciano, Daniel A.,Heflich, Robert H.
, p. 195 - 202 (2001)
N-Hydroxy-2-acetylaminofluorene (N-OH-AAF)is the proximate carcinogenic metabolite of the powerful rat liver carcinogen 2-acetylaminofluorene. In this study, transgenic Big Blue rats were used to examine the relationship between in vivo mutagenicity and DNA adduct formation by N-OH-AAF in the target liver compared with that in nontarget tissues. Male rats were given one, two, or four doses of 25 mg N-OH-AAF/kg body weight by i.p. injection at 4-day intervals, and groups of treated and control rats were euthanized up to 10 weeks after beginning the dosing. Mutant frequencies were measured in the spleen lymphocyte hprt gene, and lacl mutant frequencies were determined in the liver and spleen lymphocytes. At 6 weeks after beginning the dosing, the hprt mutant frequency in spleen lymphocytes from the four-dose group was 16.5 × 10-6 compared with 3.2 × 10-6 in control animals. Also at 6 weeks, rats given one, two, or four doses of N-OH-AAF had lacl mutant frequencies in the liver of 97.6, 155.6, and 406.8 × 10-6, respectively, compared with a control frequency of 25.7 × 10-6; rats given four doses had lacl mutant frequencies in spleen lymphocytes of 55.8 × 10-6 compared with a control frequency of 20.4 × 10-6. Additional rats were evaluated for DNA adduct formation in the liver, spleen lymphocytes, and bone marrow by 32P-postlabeling. Adduct analysis was conducted 1 day after one, two, and four treatments with N-OH-AAF, 5 days after one treatment, and 9 days after two treatments. N-(Deoxyguanosin-8-yl)-2-aminofluorene was the major DNA adduct identified in all the tissues examined. Adduct concentrations increased with total dose to maximum values in samples taken 1 day after two doses, and remained essentially the same after four doses. In samples taken after four doses, adduct levels were 103, 28, and 7 fmol/μg of DNA in liver, spleen lymphocytes, and bone marrow, respectively. The results indicate that the extent of both DNA adduct formation and mutant induction correlates with the organ specificity for N-OH-AAF carcinogenesis in the rat. Published 2001 Wiley-Liss, Inc.
Synthesis of site-specific damaged DNA strands by 8-(acetylarylamino)- 2′-deoxyguanosine adducts and effects on various DNA polymerases
Krueger, Sarah,Meier, Chris
, p. 1158 - 1169 (2013/04/10)
Beside the predominately found 8-(arylamino)-2′-dG, 8-(acetylarylamino) damages within DNA-strands may also play an important role in the induction of chemical carcinogenesis. A synthesis pathway leading to these 8-(acetylarylamino)-dG adducts using different aromatic amines has been optimized. The 8-modified dGs were converted into the corresponding phosphoramidites and site-specifically incorporated into different oligonucleotides leading to DNA strands. Lesion-bearing hybrids of these damaged DNA-strands with complementary oligonucleotides were used to study their melting properties and their circular dichroism spectra. It was shown that no EcoRI restriction took place with the damage inside the cleavage site. Finally, three different DNA polymerases were used for primer extension studies. C8-NAc-Arylamine adducts of 2′-deoxyguanosine with various aromatic amines were synthesized by using cross-coupling reactions and converted into 3′-phosphoramidites. Site-specific damaged NarI-, EcoRI- and 20mer-oligonucleotides were prepared by automated DNA-synthesis. Biophysical properties, restriction endonuclease studies and DNA-polymerase assays were performed. Copyright
A new short and efficient synthetic route to C8-N-acetylarylamine 2′-deoxyguanosine phosphoramidites
Boege, Nicolas,Krueger, Sarah,Schroeder, Marcus,Meier, Chris
, p. 3907 - 3914 (2008/09/18)
In addition to their C8-NH-arylamine-dG counterparts, C8-N-acetylarylamine adducts of 2′-deoxyguanosine (2′-dG) play an important role in the possible induction of chemical carcinogenesis. A new synthetic pathway of this adduct type using different aromatic amines has been developed following most probably an electrophilic amination reaction. These adducts can be converted into the corresponding phosphoramidites for incorporation into oligonucleotides. Georg Thieme Verlag Stuttgart.
Nucleophilic Aromatic Substitution on Ester Derivatives of Carcinogenic N-Arylhydroxamic Acids by Aniline and N,N-Dimethylaniline
Novak, Michael,Rangappa, Kanchugarakoppal S.,Manitsas, Rebecca K.
, p. 7813 - 7821 (2007/10/02)
Decomposition of N-(pivaloyloxy)-2-(acetylamino)fluorene (1b) and N-(sulfonatooxy)-4-(acetylamino)biphenyl (2a) in MeOH occurs predominately via N-O bond cleavage to yield oxazoles (5, 6, 23), methoxy adducts (7, 8, 24, 25, 26), and rearrangement products
Nucleophilic Substitution on the Ultimate Hepatacarcinogen N-(Sulfonatooxy)-2-(acetylamino)fluorene by Aromatic Amines
Novak, Michael,Rangappa, Kanchugarakoppal S.
, p. 1285 - 1290 (2007/10/02)
The kinetics and products of the reactions of the title compound 1 with aniline (5) and N,N-dimethylaniline (6) were investigated in MeOH.Addition of 5 (0.1-0.4 M) to a solution of 1 in MeOD-d4 has no effect on the overall rate of decomposition of 1 but generates a number of adducts (20-24) in moderate to high yield.The yields of all solvolysis products, except the rearranged O-sulfates 18 and 19, are suppressed by the addition of 5.The kinetic and product data are consistent with an SN1 mechanism (Scheme IV) in which 18 and 19 are generated by internal return from a tight ion pair, but all other products are generated by nucleophilic attack on a free nitrenium ion or solvent separated ion pair.The reaction of 6 with 1 shows similar characteristics to that of 5 with the exception that 6 reduces 1 in moderate yield to generate 2-(acetylamino)fluorene (25).This reduction occurs in competition with reaction to generate adducts (26, 27) similar to those obtained with 5.Kinetic and product data indicate that 25 is generated by reaction of 6 with a nitrenium ion intermediate.The differences in the behavior of 5 and 6 may be explained by cyclic voltammetry results which show that 6 is oxidized in MeOH more readily than 5 by about 2.5 kcal/mol.The reaction of 1 with 5 and 6 is considerably different from the rections of the same amines with the N-aryl-O-pivaloylhydroxylamines, which were previously shown to proceed via an SN2 mechanism.This change in mechanism may be attributed, in part, to increased steric hindrance at the nitrogen of 1 due to the N-acetyl group.
Interaction and Reactivity of Carcinogenic N-Acetyl-N-(acyloxy)-2-aminofluorene with Deoxyguanosine. An Intramolecular Approach
Defrancq, Eric,Pelloux, Nadia,Leterme, Anne,Lhomme, Marie-France,Lhomme, Jean
, p. 4817 - 4819 (2007/10/02)
Solvolysis of 3 in water-acetone mixtures yields the "adduct" 4 (65percent in water) with product and rate data consistent with the hypothesis that hydrophobic guanine-fluorene stacking, similar to that which occurs when the carcinogenic animofluorene metabolite is intercalated in DNA, is responsible for selective binding of the carcinogen at the C-8 guanine center.
N-Arylhydroxamic Acids: Reaction of Nitroso Aromatics with α-Oxo Acids
Sakamoto, Yasuko,Yoshioka, Tadao,Uematsu, Takayoshi
, p. 4449 - 4453 (2007/10/02)
A practical and high-yielding route to N-arylhydroxamic acids from nitroso aromatics and α-oxo acids 1a-d is desctibed.In aqueous and acetic acid containing media, the reactions exhibit second-order reaction kinetics overall.In the aqueous medium, the rate constant (kobsd) for N-phenylacetohydroxamic acid (8b) formation increased with increasing +>, though there were some side pathways involving azoxybenzene formation.In general, kobsd for the reaction in the acetic acid containing medium was about one-tenth of that in HCl at pH 0.6.On a preparative scale, acetic acid is better than HCl, in that both reactants showed sufficient solubilities in acetic acid for a high reaction velocity and no side reaction was detected.With this method, the proximate carcinogens, N-(4-biphenylyl)acetohydroxamic acid (12b) and N-(2-fluorenyl)acetohydroxamic acid (13b), could be easily prepared.Under both conditions, the order of kobsd for the reactions of nitrosobenzene (2) with α-oxo acids 1a-d was glyoxylic (1a) > pyruvic (1b) 2-oxobutyric (1c) > benzoylformic (1d) acid.For the reactions of substituted nitrosobenzenes 3-6 with pyruvic acid (1b), the order of kobsd was p-phenyl (6) > unsubstituted (2) > p-chloro (5) > m-chloro (4) >> o-chloro (3) nitrosobenzene.The negative Hammett reaction constant value obtained indicates that an electron-donating substituent is preferable for the reaction.The reaction mechanism and other factors affecting N-arylhydroxamic acid formation are also descussed.
Novel Synthesis and Spectral Characterization of an N-Acetoxyarylamine: N-Acetoxy-2,4-dinitrophenylamine
Huggett, Anthony C.,Cone, James L.,Thorgeirsson, Snorri S.,Roller, Peter P.
, p. 4933 - 4937 (2007/10/02)
N-Acetoxyarylamines have been proposed as reactive metabolites of carcinogenic aromatic amines.As a model compound to investigate the synthesis and spectral characteristics of these proposed intermediates, stable crystalline N-acetoxy-2,4-dinitrophenylami
Mechanism-Based Inactivation of N-Arylhydroxamic Acid N,O-Acyltransferase by 7-Substituted-N-hydroxy-2-acetamidofluorenes
Marhevka, Virginia C.,Ebner, Nancy A.,Sehon, Russell D.,Hanna, Patrick E.
, p. 18 - 24 (2007/10/02)
N-Arylhydroxamic acid N,O-acyltransferase (AHAT) catalyzes the transfer of the N-acetyl group from N-arylhydroxamic acids to arylamines.In the absence of an arylamine acceptor, AHAT catalyzes the conversion of N-arylhydroxamic acids to reactive electrophilic intermediates that become irreversibly bound to cellular nucleophiles, including those present on AHAT itself.As a part of an investigation of the AHAT-catalyzed bioactivation process, a series of 7-substituted analogues of N-hydroxy-2-acetamidofluorene (1) was synthesized and evaluated in vitro as substrates andinactivators of a partially purified hamster hepatic AHAT preparation.All of the compounds functioned as acetyl donors in the AHAT-catalyzed transacetylation of 4-aminoazobenzene (AAB) and all of them were inactivators of AHAT.The inactivation process exhibited apparent first-order kinetics, and the 7-methoxy compound exhibited the largest inactivation rate constant.Quantitative structure-activity analysis provided support for the concept that positively charged species are involved in the inactivation of AHAT by this series of compounds.Results of experiments in which nucleophilic trapping agents such as glutathione, cysteine, methionine, guanosine phosphate, and tRNA were included in incubation mixtures with AHAT and the N-arylhydroxamic acids indicated that electrophiles which diffuse away from the enzyme active site participate in the inactivation process.
