152785-98-3

Upstream product

• 961-07-9 2'-Deoxyguanosine 
• 88847-89-6 7,8-dihydro-8-oxo-2'-deoxyguanosine 

Downstream Products

• 220142-18-7 (S)-2-Amino-9-[(2R,4S,5R)-5-[bis-(4-methoxy-phenyl)-phenyl-methoxymethyl]-4-(tert-butyl-dimethyl-silanyloxy)-tetrahydro-furan-2-yl]-4-hydroxy-4,9-dihydro-1H-purine-6,8-dione 
• 220142-17-6 (R)-2-Amino-9-[(2R,4S,5R)-5-[bis-(4-methoxy-phenyl)-phenyl-methoxymethyl]-4-(tert-butyl-dimethyl-silanyloxy)-tetrahydro-furan-2-yl]-4-hydroxy-4,9-dihydro-1H-purine-6,8-dione 

Relevant academic research and scientific papers

Peroxidase-catalyzed oxidative damage of DNA and 2′-deoxyguanosine by model compounds of lipid hydroperoxides: Involvement of peroxyl radicals

The peroxidase-catalyzed decomposition of 3-hydroperoxy-1-butene (1), 2,3-dimethyl-3-hydroperoxy-1-butene (2), tert-butyl hydroperoxide (3), ethyl oleate hydroperoxide 4, and linoleic acid hydroperoxide 5 was applied as a chemical model system to assess whether lipid hydroperoxides may cause DNA damage under peroxidase catalysis. For this purpose, the Coprinus peroxidase (CIP), horseradish peroxidase (HRP), and the physiologically important lactoperoxidase (LP) were tested. Indeed, hydroperoxides 1-5 induce strand breaks in pBR 322 DNA upon peroxidase catalysis. For the nucleoside dG, the enzymatic decomposition of hydroperoxides 1-4 led to significant amounts of 4,8-dihydro-4-hydroxy-8-oxo-2′deoxyguanosine (4-HO-8-oxo-dG) and guanidine-releasing products (GRP), whereas 7,8-dihydro-8-oxo-2′-deoxyguanosine (8-oxo-dG) was not obtained. In isolated calf thymus DNA, the efficient conversion of the guanine base (Gua) was observed. Peroxyl radicals, which are generated in situ from the hydroperoxides by one-electron oxidation with the peroxidases, are proposed as the active oxidants on the basis of the following experimental facts. (i) Radical scavengers strongly inhibit the guanine oxidation in dG and DNA and strand-break formation in the latter. (ii) EPR spectral studies with 5,5-dimethyl-1-pyrroline N-oxide (DMPO) as a spin trap confirmed the formation of peroxyl radicals. (iii) The release of molecular oxygen was demonstrated, produced through the disproportionation of peroxyl radicals. The biological relevance of these findings should be seen in the potential role of the combined action of lipid hydroperoxides and peroxidases in damaging cellular DNA through peroxyl radicals.

Singlet oxygen oxidation of 2′-deoxyguanosine. Formation and mechanistic insights

Emphasis was placed in this work on the delineation of mechanistic aspects of the singlet oxygen-mediated oxidation reactions of 2′-deoxyguanosine 1 used as a DNA model compound in aerated aqueous solution. For this purpose a thermolabile naphthalene endoperoxide derivative was used allowing the generation of [18O]-labeled singlet oxygen for dedicated mechanistic studies. The analysis and characterization of the oxidized nucleosides of the 1O2 reactions were achieved on the basis of accurate HPLC-tandem mass spectrometry measurements. Thus it was found that primary oxidation products include, in addition to the previously identified 8-oxo-7,8-dihydro-2′-deoxyguanosine 5 and the two diastereomers of spiroiminodihydantoin 8, two relatively minor nucleosides, namely the two diastereomers of 4-hydroxy-8-oxo-4,8-dihydro-2′-deoxyguanosine 9.

Mechanistic and kinetic aspects of photosensitization in the presence of oxygen

Determining whether the first step of photooxygenation is Type I or Type II is a necessary prerequisite in order to establish the mechanism of photodynamic action. But this distinction is not sufficient, because other processes, both consecutive and competitive, commonly participate in the overall mechanism. Thus, in both Type I and Type II reactions, the initial products are often peroxides that can break down and induce free radical reactions. These aspects of photosensitization are discussed and illustrated by sensitizer/substrate systems involving (1) only radical reactions (decatungstate/alkane) and (2) reactions of singlet oxygen occurring in competitive and consecutive processes and possibly followed by radical reactions (methylene blue/2′-deoxyguanosine). Two other previously investigated systems involving, respectively, a Type II interaction followed by radical processes (methylene blue/alkene) and Type II reactions, some of which being competitive or consecutive (rose bengal/alkene), are briefly reconsidered.

Oxidative DNA damage by radicals generated in the thermolysis of hydroxymethyl-substituted 1,2-dioxetanes through the α cleavage of chemiexcited ketones

The 3-(hydroxymethyl)-3,4,4-trimethyl-1,2-dioxetane (HTMD) highly efficiently damages DNA compared to the merely alkyl-substituted derivative 3,3,4,4-tetramethyl-1,2-dioxetane (TMD). To elucidate this difference in oxidative reactivity, two additional hydroxymethyl-substituted 1,2- dioxetanes, namely cis/trans-3-(hydroxymethyl)-3,4-dimethyl-4-(phenylmethyl)- (lα/1β) and 3-(hydroxymethyl)-4,4-dimethyl-3(phenylmethyl)-1,2-dioxetane (2), were investigated in regard to their photochemical and photobiological properties. The high genotoxic effects of the hydroxymethyl-substituted 1,2- dioxetanes, which are reflected in the significant formation of single- strand breaks in plasmid pBR 322 DNA and the efficient oxidation of guanine in calf thymus DNA and the nucleoside 2'-deoxyguanosine (dGuo), are for the first time understood in terms of radical chemistry. The reactivity order of the dioxetanes 1α/1β > HTMD > 2 >> TMD to damage DNA parallels the propensity of these dioxetanes to generate radicals. These reactive species are formed in the thermolysis of the dioxetanes through α cleavage of the intermediary triplet-excited α-hydroxy- and α-phenyl-substituted carbonyl products. The presence of radicals was confirmed by spin-trapping experiments with 5,5-dimethyl-1-pyrroline N-oxide and by laser-flash photolysis. These carbon-centered radicals are efficiently scavenged by molecular oxygen to produce peroxyl radicals, which are proposed as the active DNA damaging species in the thermal decomposition of the hydroxymethyl-substituted 1,2- dioxetanes HTMD, 1α/1β, and 2.

Photochemistry and photobiology of furocoumarin hydroperoxides derived from imperatorin: Novel intercalating photo-fenton reagents for oxidative DNA modification by hydroxyl radicals

Photochemical and photobiological properties of the imperatorin-derived furocoumarin hydroperoxides 1a, 1a′, 2a and 2a′ have been investigated. Irradiation (350 nm) of the hydroperoxide 2a′ afforded the alcohol 2b (2%), a diastereomeric mixture of the hydroxy epoxide 2c (40%; diastereomeric ratio = 80:20) and the epoxide 2d (8%). The formation of these products was rationalized in terms of homolysis of the hydroperoxide bond initiated by intramolecular energy transfer from the photoexcited furocoumarin chromophore. The quantum yields for the photolytic decomposition of hydroperoxides were estimated to be in the range of 0.03-0.85 and decreased in the order 2a ? 2a′ ? 1a′ ≥ 1a. The involvement of hydroxyl radicals in these reactions was established by trapping experiments with benzene and spectroscopic evidence was obtained by EPR spin trapping with 5,5-dimethylpyrroline-N-oxide. Fluorescence titration, DNA melting and linear dichroism studies of furocoumarins indicated that these compounds undergo efficient complexation and also intercalation into the DNA. The binding parameters K (intrinsic binding constant) and 1/n (frequency of binding sites) of complexes between furocoumarin derivatives and DNA were determined to be in the range of 3900-23900 M-1 and 0.017-0.045. The photoreaction of 1a′ and 1b′ with 2′-deoxyguanosine (dGuo) afforded exclusively 7,8-dihydro-8-oxo-2′-deoxy-guanosine (8-oxodGuo), presumably through singlet oxygen, which was formed in a type II photooxidation process. In contrast, the hydroperoxide 2a oxidized dGuo to oxazolone as major and 8-oxodGuo as minor products through hydroxyl radicals, which were generated from 2a under photolytic conditions. Interestingly, the photoreactions of furocoumarins with salmon testes DNA showed that the highly reactive (φ = 0.85) hydroperoxide 2a is also most efficient in inducing the mutagenic DNA oxidation product 8-oxodGuo. Hence, the novel furocoumarin hydroperoxide 2a constitutes the first intercalating photo-Fenton reagent and serves as convenient hydroxyl radical source for genotoxicity studies.

Photooxiation of 8-oxo-7,8-dihydro-2'-deoxyguanosine by thermally generated triplet-excited ketones from 3-(hydroxymethyl)-3,4,4-trimethyl-1,2-dioxetane and comparison with type I and type II photosensitizers

Calf thymus DNA and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) were photooxidized in the dark by triplet-excited ketones generated in the thermal decomposition of 3-(hydroxymethyl)-3,4,4-trimethyl-1,2-dioxetane (HTMD). The oxidation of DNA led to 8-oxodGuo and the type I photooxidation product 2,2-diamino[2-deoxy-β-D-erythro-pentofuranosyl)-4-amino]-5(2H)-oxazol one (oxazolone). While the yield of oxazolone progressively increased, 8-oxodGuo was substantially consumed in DNA on successive exposure to HTMD. The oxidation of authentic 8-oxodGuo by HTMD and established photosensitizers such as benzophenone (mainly type I) and Rose Bengal (predominantly type II) was studied in detail in regard to the concentration and time dependence and the influence of D2O versus H2O. The singlet-oxygen-derived 4R* and 4S* diastereomers of 4-hydroxy-8-oxo-4,8-dihydro-2'-deoxyguanosine (4-HO-8-oxodGuo) and oxazolone were the major products. A substantial kinetic D2O effect (ca. 10-fold) in the Rose Bengal-photosensitized degradation of 8-oxodGuo unequivocally established that in this case singlet oxygen (type II photooxidation) is involved. However, the efficient formation of oxazolone by benzophenone as a characteristic type I photooxidant, as well as in the HTMD-mediated oxidation (predominantly type I), and the fact that these processes exhibit a negligible D2O effect provide cogent experimental evidence for an electron or hydrogen atom transfer mechanism (type I photooxidation) in the oxidative degradation of 8-oxodGuo into oxazolone. The unprecedented observation that comparable product ratios of 4-HO-8-oxodGuo and oxazolone were obtained in the 8-oxodGuo oxidations, irrespective of whether Rose Bengal as a typical type II photooxidant or benzophenone as an established type I photooxidant was employed, is presumably due to electron-transfer chemistry of 1O2 with the easily oxidized 8-oxodGuo in view of its low oxidation potential. This nicely accounts for the fact that the primary oxidation product 8-oxodGuo, which serves as an important monitor of oxidative genotoxicity, may not accumulate appreciably in the photooxidation of DNA.

Photooxydation sensibilisee de la desoxy-2' guanosine par des phtalocyanines et naphtalocyanines. Determination de l'importance des mecanismes de type I et de type II

The photodynamic properties of sulfonated derivatives of phthalocyanine and naphthalocyanine were investigated using 2'-deoxyguanosine as a model compound for DNA.The major degradation photoproducts of this nucleoside were characterized and classified into two categories.The degradation involving the radical mechanism (type I) led to the formation of 2,2-diamino-5-oxazolone.The two main photooxidation products involving type II mechanism were characterized as the 4R* and 4S* diastereoisomers of 9-(2-β-D-deoxyerythropentofuranosyl)-4,8-dihydro-4-hydroxy-8-oxoguanine.In addition, 8-oxo-7,8-dihydro-2'-deoxyguanosine was shown to be generated (probably through type II mechanism).By identifying and quantifying these photoproducts, the ratio of type I/type II photoprocess was established for three (aluminum, gallium and zinc) disulfonated phthalocyanines and a tetrasulfonated aluminum naphthalocyanine.It was found that the type II mechanism is predominant.