117182-88-4Relevant academic research and scientific papers
Oxidative damage to DNA constituents by iron-mediated Fenton reactions: The deoxyadenosine family
Chattopadhyaya, Rajagopal,Goswami, Bhaswati
, p. 394 - 406 (2012)
The effect of exposing 2′-deoxyadenosine (dA), 5′-dAMP, 3′-dAMP, dApA, dA(pdA)19, and poly(dA): oligo(dT) to iron/H2O2 in the presence and absence of ethanol or NADH has been studied. HPLC retention times, enzyme treatments, radiolabeled substrates, UV absorption spectra, and fast atom bombardment mass spectrometry (FABMS) have been used to distinguish 20 products arising from the reaction, of which 16 have been identified and four anomers proposed by comparison with earlier gamma radiation studies. The radical responsible for the reactions seems to be analogous to radiation-derived ·OH, has many products in common, but has some novel ones probably specific for Fenton-induced damage. Two new dimeric adducts arising from the generation of hydroxylamine at N7 and its subsequent condensation with two known sugar damage products, dR-adenine-N1-oxide, and two isomers of dR-FAPy arising from radical attacks at C4 and C5, may be considered novel in the present study. Unlike radiation-derived ·OH, the radical under study is difficult to eliminate due to its generation in the proximity of the substrate molecules. It is proposed that the iron binds to the phosphate group and generates the radical in its vicinity. Strand breaks in dA(pdA)11 resulting from the Fenton reaction are of two types, spontaneous and alkali-labile. Duplex DNA is less sensitive to attack by this radical, as its various degradation products are a subset of those obtained with monomer substrates and only dR-FAPy production is relatively enhanced for poly (dA): oligo (dT) as compared to those from other substrates. Copyright
Model studies of DNA C5′ radicals. Selective generation and reactivity of 2′-deoxyadenosin-5′-yl radical
Chatgilialoglu, Chryssostomos,Guerra, Maurizio,Mulazzani, Quinto G.
, p. 3839 - 3848 (2003)
The reaction of hydrated electrons (eaq-) with 8-bromo-2′-deoxyadenosine has been investigated by radiolytic methods coupled with product studies and addressed computationally by means of DFT-B3LYP calculations. Pulse radiolysis revealed that this reaction was complete in ～0.3 μs, and, at this time, no significant absorption was detected. The spectrum of a transient developed in 20 μs has an absorbance in the range 300-500 nm (εmax? 9600 M-1 cm-1 at 360 nm), and it was assigned to aromatic aminyl radical 3. Computed vertical transitions (TD-UB3LYP/6-311+G*) are in good agreement with the experimental observations. Radical 3 is obtained by the following reaction sequence: one-electron reductive cleavage of the C-Br bond that gives the C8 radical, a fast radical translocation from the C8 to C5′ position, and an intramolecular attack of the C5′ radical at the C8,N7 double bond of the adenine moiety. The rate constant for the cyclization is 1.6 × 105 s-1. On the basis of the theoretical findings, the cyclization step is highly stereospecific. The rate constants for the reactions of C5′ and aminyl 3 radicals with different oxidants were determined by pulse radiolysis methods. The respective rate constants for the reaction of 2′-deoxyadenosin-5′-yl radical with dioxygen, Fe(CN)63-, and MV2+ in water at ambient temperature are 1.9 × 109, 4.2 × 109, and 2.2 × 108 M-1 s-1. The value for the reaction of aminyl radical 3 with Fe(CN)63- is 8.3 × 108 M-1 s-1, whereas the reaction with dioxygen is reversible. Tailored experiments allowed the reaction mechanism to be defined in some detail. A synthetically useful radical cascade process has also been developed that allows in a one-pot procedure the conversion of 8-bromo-2′-deoxyadenosine to 5′,8-cyclo-2′-deoxyadenosine in a diastereoisomeric ratio (5′R):(5′S) = 6:1 and in high yield, by reaction with hydrated electrons in the presence of K4Fe(CN)6.
Radiation-induced formation of purine 5′,8-cyclonucleosides in isolated and cellular DNA: High stereospecificity and modulating effect of oxygen
Belmadoui, Nourreddine,Boussicault, Fabien,Guerra, Maurizio,Ravanat, Jean-Luc,Chatgilialoglu, Chryssostomos,Cadet, Jean
experimental part, p. 3211 - 3219 (2010/08/21)
The present work is aimed at gaining conclusive mechanistic insights into the radiation-induced formation of the 5′R and 5′S diastereomers of both adenine and guanine 5′,8-cyclo-2′-deoxyribonucleosides, with emphasis on the delineation of the inhibitory effect of O2 in isolated and cellular DNA. The levels of purine 5′,8-cyclo-2′- deoxyribonucleosides as assessed by HPLC-MS/MS were found to decrease steadily with the increase of O2 concentration, the 5′,8-cyclo-2′- deoxyguanosine being produced more efficiently than the 5′,8-cyclo- 2′-deoxyadenosine for low O2 concentrations. A high stereoselectivity was observed in the intramolecular addition of the C5′ radical to the C8 of the purine leading, after the creation of the C5′-C8 bond and a subsequent oxidation step, to the predominant formation of the 5′R diastereomer for both purine 5′,8-cyclonucleosides. The reduced formation yield of the 4 tandem lesions in the presence of O2 explains, at least partly, the low efficiency of radiation-induced yields of the purine 5′,8-cyclo-2′-deoxyribonucleosides in cellular DNA, which are about two orders of magnitude lower than the previously reported data obtained from HPLC-MS analysis. The Royal Society of Chemistry 2010.
C5′-adenosinyl radical cyclization. A stereochemical investigation
Navacchia, Maria Luisa,Chatsilialoglu, Chryssostomos,Montevecchi, Pier Carlo
, p. 4445 - 4452 (2007/10/03)
A variety of substituted 2′-deoxyadenosin-5′-yl radicals 3 were generated under different reaction conditions. Radicals 3 underwent intramolecular cyclization onto the C8-N7 double bond of the adenine moiety leading to aminyl radicals (5′S,8R)-4 and (5′R,8R)-4 and, eventually, to the corresponding cyclonucleosides 5 and 6. The effect of the solvent, the nature of the substituents, and the generation method of radicals 3 on the stereoselectivity of the C5′-radical cyclization have been considered. The observed increase of the (5′S)/(5′R) ratio by increasing the bulkiness of the R1 group is explained in terms of steric repulsion between R1 and the purine moiety which favors the C5′-endo conformation, whereas the effect of the water solvent in promoting the (5′R)-stereoselective cyclization is ascribed to intermolecular hydrogen bonding stabilizing the C5′-exo confomation.
