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Distribution of methyl and ethyl adducts following alkylation with monofunctional alkylating agents.Mutation Research Jul 1990Alkylating agents, because of their ability to react directly with DNA either in vitro or in vivo, or following metabolic activation as in the case of the... (Review)
Review
Alkylating agents, because of their ability to react directly with DNA either in vitro or in vivo, or following metabolic activation as in the case of the dialkylnitrosamines, have been used extensively in studying the mechanisms of mutagenicity and carcinogenicity. Their occurrence is widespread in the environment and human exposure from natural and pollutant sources is universal. Since most of these chemicals show varying degrees of both carcinogenicity and mutagenicity, and exhibit compound-specific binding patterns, they provide an excellent model for studying molecular dosimetry. Molecular dosimetry defines dose as the number of adducts bound per macromolecule and relates the binding of these adducts to the human mutagenic or carcinogenic response. This review complies DNA alkylation data for both methylating and ethylating agents in a variety of systems and discusses the role these alkylation products plays in molecular mutagenesis.
Topics: Alkylating Agents; Alkylation; Animals; Carcinogenicity Tests; DNA; Humans; Methylation; Mutagenicity Tests; Mutation
PubMed: 2195323
DOI: 10.1016/0027-5107(90)90173-2 -
Chemico-biological Interactions Jul 2001The Ames test and the SOS-chromotest are widely used bacterial mutagenicity/genotoxicity assays to test potential carcinogens. Though the molecular mechanisms leading to...
On the role of alkylating mechanisms, O-alkylation and DNA-repair in genotoxicity and mutagenicity of alkylating methanesulfonates of widely varying structures in bacterial systems.
The Ames test and the SOS-chromotest are widely used bacterial mutagenicity/genotoxicity assays to test potential carcinogens. Though the molecular mechanisms leading to backmutations and to the induction of SOS-repair are in principle known the role of alkylation mechanisms, of different DNA-lesions and of DNA-repair is in parts still unknown. In this study we investigated 14 monofunctional methanesulfonates of widely varying structures for mutagenicity in Salmonella typhimurium strain TA 1535 sensitive for O(6)-guanine alkylation for comparison with strain TA 100 in order to obtain additional information on the role of alkylation mechanisms, formation of the procarcinogenic DNA-lesion O(6)-alkylguanine and the role of DNA-repair in induction of backmutation. The substances were also tested in the SOS-chromotest with Escherichia coli strain PQ 37 and strain PQ 243 lacking alkyl base glycosylases important for base excision repair in order to examine the role of alkylation mechanisms, of base excision repair and the role of O-alkyl and N-alkyl DNA-lesions on the induction of SOS-repair. The secondary methanesulfonates with very high S(N)1-reactivity isopropyl methanesulfonate and 2-butyl methanesulfonate showed highest mutagenicities in both strains. The higher substituted methanesulfonates with very high S(N)1-reactivity had lower mutagenic activities because of reduced half lives due to their high hydrolysis rates. A clear increase in mutagenicities in strain TA 100 was observed for the primary compounds methyl methanesulfonate and allyl methanesulfonate with very high S(N)2-reactivity. The primary compound phenylethyl methanesulfonate has a relatively high mutagenicity in both Salmonella strains which can be explained by an increased S(N)1-reactivity and by low repair of the O(6)-phenylethylguanine. Highest SOSIPs (SOS inducing potency) in strains PQ 37 and PQ 243 were found for methyl methanesulfonate and for the secondary compounds with high S(N)1-reactivity. The ratios in the SOSIPs between strain PQ 243 and PQ 37, indirectly indicative for the role of O- and N-alkylation in the induction of SOS-repair, was high for the primary methanesulfonates and lower for the secondary, indicating that the SOS-repair is, to a certain extent, also induced by other lesions than O(6)-alkylation. The results indicate that O(6)-alkylation is also a predominant lesion for backmutation in strain TA 100 and that in the case of monofunctional alkylating agents high S(N)2-reactivities are required to induce error prone repair mediated backmutations. The O(6)-alkylguanine lesion is also important for induction of SOS-repair in the SOS-chromotest, however, other sites of alkylation which are repaired by the base pair excision repair system can also efficiently contribute to the induction of SOS-repair.
Topics: Alkylating Agents; Alkylation; DNA Repair; Mesylates; Molecular Structure; Mutagenicity Tests; Mutagens; Salmonella typhimurium
PubMed: 11518566
DOI: 10.1016/s0009-2797(01)00211-3 -
Molekuliarnaia Biologiia 1975Kinetics of DNA alkylation with 2',3'-o-[N-2-chloroethyl-N-methylamino)benzylidene]uridine (UCHRCL), uridine-5'-methylphosphate (MepUCHRCL) and...
Kinetics of DNA alkylation with 2',3'-o-[N-2-chloroethyl-N-methylamino)benzylidene]uridine (UCHRCL), uridine-5'-methylphosphate (MepUCHRCL) and 4-(N-2-chloroethyl-N-methylamino)benzylamine (NH2CH2RCl) and kinetics of elimination of alkylated bases have been studied. Efficiency of DNA alkylation (p/s-ratio of rate constant of alkylation to the sum of rate constants of by-reactions of an active intermediate formed from the reagent) increases with an increase of the positive charge of the reagents as well as efficiency of tRNA alkylation. Alkylated bases are eliminated from DNA; rate of elimination depends on the structure of the reagent; it decreases in the series NH2CH2R- greater than greater than UCHR-greater than MepUCHR-. Bases alkylated by NH2CH2RCl and UCHRCl are eliminated from DNA during alkylation; therefore plots of DNA alkylation by NH2CH2RCl have a maximum. DNA alkylated by MepUCHRCl is rather stable; alkylated bases are not eliminated during alkylation. Effect of temperature and pH on elimination has been studied.
Topics: Alkylating Agents; Benzylidene Compounds; Binding Sites; DNA; Hydrogen-Ion Concentration; Kinetics; Methylamines; Nucleic Acid Conformation; Structure-Activity Relationship
PubMed: 2860
DOI: No ID Found -
Cancer Research Dec 1987
Review
Topics: Alkylating Agents; Alkylation; Animals; Carcinogens; Chromatin; DNA Damage; DNA Repair; DNA, Mitochondrial; Humans; Mammals; Nucleic Acid Conformation; Oncogenes; Proto-Oncogenes; Repetitive Sequences, Nucleic Acid; Tetrahydrofolate Dehydrogenase; Transcription, Genetic
PubMed: 3315187
DOI: No ID Found -
Mutation Research Feb 1970
Topics: Alkylating Agents; Alkylation; Bacillus subtilis; Chromatography, DEAE-Cellulose; DNA, Bacterial; Guanine; Methylation; Mutation; Transformation, Genetic
PubMed: 4984020
DOI: 10.1016/0027-5107(70)90052-7 -
Biochimica Et Biophysica Acta Oct 1981The widespread occurrence of physical binding between biological macromolecules and small molecules has prompted us to hypothesize that physical binding contributes to...
The widespread occurrence of physical binding between biological macromolecules and small molecules has prompted us to hypothesize that physical binding contributes to DNA alkylation specificity. The preferred physical binding sites for a CH+3-like test probe were predicted for several sequences of DNA using molecular mechanics free space calculation methods. Sequences containing A = T basepairs direct physical binding to the minor groove, whereas sequences containing G identical to C basepairs direct physical binding to the major groove. Physical binding calculations were also performed for model 'unwound' DNA conformations. The results of the test probe studies were subsequently employed as starting points to predict the preferred physical binding sites for the more complicated case of an actual alkylating agent, the dimethylaziridinium ion. These studies demonstrate that physical binding specificity is highly dependent upon DNA sequence and conformation, and correlates well with the DNA alkylation site specificity observed for alkylating agents in th dimethylaziridine class.
Topics: Adenine; Alkylating Agents; Alkylation; Base Composition; Base Sequence; Cytosine; DNA; Guanine; Models, Molecular; Nucleic Acid Conformation; Thymine
PubMed: 7284397
DOI: 10.1016/0005-2787(81)90055-1 -
Die Naturwissenschaften Aug 1970
Topics: Alkylating Agents; Animals; Cattle; Chromatography; DNA; In Vitro Techniques; Insecticides; Phosphoric Acids; Thymus Gland
PubMed: 5447862
DOI: 10.1007/BF00599981 -
Synthesis, characterization and chemoprotective activity of polyoxovanadates against DNA alkylation.Journal of Inorganic Biochemistry Mar 2012The alkylation of pUC19 plasmid DNA has been employed as a model reaction for the first studies on chemoprotective action by a mixed-valence (+IV/+V) polyoxovanadate. A...
The alkylation of pUC19 plasmid DNA has been employed as a model reaction for the first studies on chemoprotective action by a mixed-valence (+IV/+V) polyoxovanadate. A new, non-hydrothermal route for the high yield preparation of the test compound is described. The deep green, microcrystalline solid A was isolated after a three-day reaction in water at 80°C and 1 atm, while the reaction at 100°C gave green crystals of B. Both solids were structurally characterized by X-ray diffractometry and FTIR, EPR, NMR and Raman spectroscopies. Product A was identified as (NH(4))(2)V(3)O(8), while B corresponds to the spherical polyoxoanion [V(15)O(36)(Cl)](6-), isolated as the NMe(4)(+) salt. The lack of solubility of A in water and buffers prevented its use in DNA interaction studies, which were then carried out with B. Complex B was also tested for its ability to react with DNA alkylating agents by incubation with diethylsulphate (DES) and dimethylsulphate (DMS) in both the absence and presence of pUC19. For DMS, the best results were obtained with 10 mM of B (48% protection); with DES, this percentage increased to 70%. The direct reaction of B with increasing amounts of DMS in both buffered (PIPES 50 mM) and non-buffered aqueous solutions revealed the sequential formation of several vanadium(IV), vanadium(V) and mixed-valence aggregates of different nuclearities, whose relevance to the DNA-protecting activity is discussed.
Topics: Alkylating Agents; Crystallography, X-Ray; DNA; Magnetic Resonance Spectroscopy; Plasmids; Solubility; Sulfuric Acid Esters; Vanadium
PubMed: 22265837
DOI: 10.1016/j.jinorgbio.2011.11.019 -
Chemico-biological Interactions Jan 2000Styrene 7,8-oxide (SO), a major metabolite of styrene, is classified as a probable human carcinogen. In the present work, salmon testis DNA was reacted with SO and the... (Comparative Study)
Comparative Study
Styrene 7,8-oxide (SO), a major metabolite of styrene, is classified as a probable human carcinogen. In the present work, salmon testis DNA was reacted with SO and the alkylation products were analysed after sequential depurination in neutral or acidic conditions followed by HPLC separation and UV-detection. A novel finding was that the N-3 position of adenine was the next most reactive alkylation site in double-stranded DNA, comprising 4% of the total alkylation, as compared to alkylation at the N-7 position of guanine, 93% of the total alkylation. Both alpha- and beta-products of SO were formed at these two sites. Other modified sites were N2-guanine (1.5%, alpha-isomer), 1-adenine (0.4%, both isomers) and N6-adenine (0.7%, both isomers) as well as 1-hypoxanthine (0.1%, alpha-isomer), formed by deamination of the corresponding 1-adenine adduct. The results indicated that in double-stranded DNA N-7 of guanine and N-3 of adenine account for 97% of alkylation by SO. However, these abundant adducts are not stable, the half-life of depurination in DNA for 3-substituted adenines being approximately 10 and approximately 20 h, for alpha- and beta-isomers, respectively, and 51 h for both isomers of 7-substituted guanines.
Topics: Adenine; Alkylating Agents; Alkylation; Animals; Carcinogens; Chromatography, High Pressure Liquid; DNA; DNA Adducts; Epoxy Compounds; Guanine; Hydrogen-Ion Concentration; Hydrolysis; Male; Salmon; Testis
PubMed: 10658899
DOI: 10.1016/s0009-2797(99)00137-4 -
Chemical Communications (Cambridge,... Jan 2018It may be useful to develop prodrugs that are selectively activated by oxidative stress in cancer cells to release cell-killing reactive intermediates. However,...
It may be useful to develop prodrugs that are selectively activated by oxidative stress in cancer cells to release cell-killing reactive intermediates. However, relatively few chemical strategies exist for the activation of prodrugs under conditions of oxidative stress. Here we provide evidence for a novel process in which oxidation of a thiol residue in the natural product leinamycin E1 by HO and other byproducts of cellular oxidative stress initiates generation of an episulfonium ion that selectively alkylates guanine residues in duplex DNA.
Topics: Alkylation; Antineoplastic Agents, Alkylating; DNA; DNA Damage; Ferric Compounds; Guanine; Hydrogen Peroxide; Lactams, Macrocyclic; Oxidation-Reduction; Prodrugs; Xanthine; Xanthine Oxidase
PubMed: 29231931
DOI: 10.1039/c7cc08482j