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Liberal Readings on Education Stefan Melnik and Sascha Tamm …

Schuster With contributions by D. Wasielewski BD The series Topics in Current Chemistry presents critical reviews of the present and future trends in modern chemical research.

The scope of coverage includes all areas of chemical science including the interfaces with related disciplines such as biology, medicine and materials science.

The goal of eaxch thematic volume is to give the nonspecialist reader, whether at the university or in industry, a comprehensive overview of an area where new insights are emerging that are of interest to a larger scientific audience.

As a rule, contributions are specially commissioned. The editors and publishers will, however, always be pleased to receive suggestions and supplementary information. Papers are accepted for Topics in Current Chemistry in English. Visit the TCC home page at http: All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other ways, and storage in data banks.

Duplication of this publication or parts thereof is only permitted under the provisions of the German Copyright Law of September 9,in its current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law. Armin de Meijere Prof. Please contact your librarian who can receive a password for free access to the full articles by registering at: Preface The central role played by DNA in cellular life guarantees a place of importance for the study of its chemical and physical properties.

It did not take long after Watson and Crick described the now iconic double helix structure for a question to arise about the ability of DNA to transport electrical charge.

It seemed apparent to the trained eye of the chemist or physicist that the array of neatly stacked aromatic bases might facilitate the movement of an electron or hole along the length of the polymer. It is now more than 40 years since the first experimental results were reported, and that question has been answered with certainty. In the last decade, an intense and successful investigation of this phenomenon has focused on its mechanism.

The experimental facts discovered and the debate of their interpretation form large portions of these volumes.

The views expressed come both from experimentalists, who have devised clever tests of each new hypothesis, and from neuberschnung, who have applied these findings and refined the powerful theories of electron transfer reactions.

Indeed, from a purely scientific view, the cooperative marriage of theory and experiment in this pursuit is a powerful outcome likely to outlast the recent intense interest in neiberechnung field. Is the quest over? No, not nearly so. The general agreement that charge can migrate in DNA is merely the conclusion of the first chapter.

This hard-won understanding raises many important new questions. Some pertain to oxidative damage of DNA and mutations in the genome. Others are related to the possible use of the charge transfer ability of DNA in the emerging field of molecularscale electronic devices.

Still others are focused on the application of this phenomenon to the development of clinical assays. It is my hope that these volumes will serve as a springboard for the next phase of this investigation.

The foundation knowledge of this field contained within these pages should serve as a defining point of reference for all who explore its boundaries. For this, I must thank all of my coauthors for their effort, insight and cooperation. Atlanta, January Gary B. The Hopping Mechanism B. Some Theoretical Notions Y. Di Felice Top Curr Chem Information is also provided on the final one-electron oxidation products of 8-oxo-7,8-dihydroguanine, an ubiquitous decomposition product of DNA with most chemical and physical oxidizing agents, that exhibits a low ionization potential, and is therefore an excellent sink for positive hole migration within double-stranded DNA.

In the second part of the review, it is shown that duplex stability plays a major role in the redistribution of positive holes generated by high intensity UV laser pulses on purine and pyrimidine bases towards guanine residues.

History of the International Atomic Energy Agency: the first forty years

These results were obtained by measurement of several oxidized nucleosides within DNA using a sensitive and accurate high performance liquid chromatography-tandem mass spectrometry assay. One-Electron Oxidation of 8-oxodGuo. Intensity Dependence on the Product Distribution. Major sources of endogenous oxidation processes include aerobic metabolism leading to the leakage of superoxide radicals from mitochondria and endoplasmic reticulum, and inflammation involving the production of reactive species by specific enzymes such as NADPH oxidase and myeloperoxidase [5].

Exogenous chemical and physical agents, including environmental carcinogens, ionizing radiation and UV-A light may also contribute to the induction of oxidative reactions. In this respect, DNA, together with other key biomolecules that include membrane lipids and proteins, appear to be critical cellular targets.


In contrast, interest in the one-electron oxidation of DNA is more recent; however, a notable exception concerns detailed investigations of the early events associated with the direct effect of ionizing radiation [for a recent review, see 10]. Major attention devoted to charge transfer reactions within DNA during the last five years has provided a strong impetus to this field of research.

As it will be discussed extensively in several chapters, most of the approaches have involved the specific generation of radical cations either at the C-4 of 2-deoxyribose or at proximal guanines within defined sequences of DNA fragments, and the investigation of hole transfer processes to distant guanine residues.

Interestingly, this has led to major achievements with the formulation of several mechanisms of transfer, such as multistep hopping, phonon-assisted polaron-like hopping, and coherent super-exchange [11—15]. A different strategy has been applied in our work, that emphasizes the importance of DNA stability on hole transfer within double-stranded DNA. This work is based on determination of the overall yield of oxidized nucleosides that arise from the conversion of initially generated purine and pyrimidine radical cations within DNA exposed to two-photon UVC laser pulses.

Evidence was provided that positive holes are located on guanine whereas electron attachment involves pyrimidine bases in g- or X-irradiated DNA after warming.

These results strongly imply the occurrence of significant electron transfer processes. This was confirmed through the identification and measurement of final degradation products resulting from the conversion of radiation-induced pyrimidine and purine radicals upon thawing the frozen solutions or dissolving the dry nucleoside samples into aqueous solutions [23—26]. However, the biochemical significance of the latter studies is challenged by the fact that the transformation of transient purine and pyrimidine radicals into diamagnetic decomposition products is oxygen-independent in the solid state.

Therefore, it is necessary to study the chemistry of one-electron nucleobase intermediates in aerated aqueous solutions in order to investigate the role of oxygen in the course of reactions that give rise to oxidation products within DNA and model compounds.

In this respect, type I photo- 4 Thierry Douki et al.

Photoexcited 2-methyl-1,4-naphthoquinone MQ has been used to efficiently generate pyrimidine radical cations 2 through one-electron oxidation of 1 [29, 32]. Two main degradation pathways that involve hydration neubfrechnung deprotonation of initially-generated thymidine radical cations 2 were proposed from isolation and characterization of the main oxidized nucleosides, including hydroperoxides and other stable decomposition products [33].

Longe-Range Charge Transfer in DNA I – PDF Free Download

The exclusive formation of four cis and trans diastereomers of 5-hydroperoxy-6hydroxy-5,6-dihydrothymidine 5 may be rationalized biubische terms of the specific generation of oxidizing 6-hydroxy-5,6-dihydrothymidyl radicals 3 [34] through hydration at C-6 of thymidine radical cations 2.

The formation of thymidine hydroperoxides probably involves fast addition of molecular oxygen to neutral 6-hydroxy-5,6-dihydrothymidyl 3 and 2-deoxyuridyl 5-methyl 9 radicals, with rates of reaction that are controlled by diffusion [32]. In subsequent steps, about half of the resulting peroxyl radicals 4,10 are reduced by superoxide radicals [28] leading to the formation of hydroperoxides 5, Depending on the presence of metal ions, the latter hydroperoxide may also transform into the four cis and trans diastereomers of 5,6-dihydroxy-5,6-dihydrothymidine ThdGly 7 and N- 2-deoxy-b-D-erythro-pentofuranosyl formamide 6.

In comparison, transformation of 5- hydroperoxymethyl 20 -deoxyuridine 11 leads to the formation of 5- hydroxymethyl -deoxyuridine 5-HMdUrd 12 and bikubksche a much lesser extent, 5-formyl -deoxyuridine 5-FordUrd Effects of Duplex Stability on Charge-Transfer Efficiency within DNA 5 Scheme 1 Reactions of the thymidine radical cation in aerated aqueous solution On the other hand, a number of thymidine oxidation products may be formed from dismutation reactions of initial peroxyl radicals 4,10 generated by the one-electron oxidation of dThd 1 by MQ-photosensitization in aerated aqueous solutions.

These reactions give rise to highly reactive oxyl radicals [34] that can either undergo hydrogen atom abstraction to give thymidine glycols 7 or undergo b scission and 5,6-pyrimidine bond cleavage with subsequent loss of a pyruvyl group.

Dismutation reactions of 10 would predominantly generate 5-formyl -deoxyuridine The structure of thymidine Thd hydroperoxides 5,11 was assigned on the basis of extensive 1H and 13C-NMR measurements and comparison to authentic compounds obtained by chemical synthesis [33].

More recently, the X-ray crystal structure of cishydroperoxyhydroxy-5,6-dihydrothymine was determined and its electronic properties were examined by ab initio theoretical investigations [39]. The mixture of the four cis and trans diastereomers of 5-hydroperoxyhydroxy-5,6-dihydrothymidine 5 was completely resolved by reversed phase high performance liquid chromatography and each of the peroxides was individually detected using a sensitive post-column reaction method [40].

Interestingly, the presence of 5- hydroperoxymethyl -deoxyuridine 11 in the enzymatic digest of oxidized DNA was recently assessed using a sensitive assay that involved combination of HPLC analysis with tandem mass spectrometry detection Ravanat and Cadet, unpublished.

The bulk of stable dThd oxidation products 6—8, 12,13 have also been identified on the basis of extensive 1H and 13C NMR, mass spectrometry and X-ray bikubksche analyses [41—47]. As will be discussed later, the measurement of oxidized nucleosides including thymidine glycols 75- hydroxymethyl -deoxyuridine 12 and 5-formyl -deoxyuridine 13 is now possible within DNA [48] using the highly and sensitive of HPLC-tandem MS assay [16—18].

It may be added that evidence for the formation of the latter two oxidized nucleosides 12,13 within DNA was provided from previous studies with type I photosensitizers, neuberechnyng menadione, riboflavin, and a nitro derivative of lysine [49—52].


It was also found, on the basis of 18O labeling experiments, that hydration of cytosine radical cations 15 predominantly occurs Effects of Duplex Stability on Charge-Transfer Efficiency within DNA 7 Scheme 2 One-electron oxydation reactions of 20 -deoxycytidine in aerated aqueous solutions 8 Thierry Douki et al.

However, isolation of the cis and trans diastereomers of 5-hydroperoxyhydroxy-5,6dihydro -deoxycytidine 18 is not possible due to their high instability. The main stable oxidation products were the four cis bikubisvhe trans diastereomers of 5,6-dihydroxy-5,6-dihydro -deoxyuridine 21 that arise from fast deamination of the initially generated cytosine glycols The glycols of dCyd 20 were recently bikybische and characterized [54]. A reasonable mechanism for the formation of dCyd glycols 20 Scheme 2 involves fast bikubiscye of molecular oxygen to 6-hydroxy-5,6-dihydrocytosyl radicals 16 [32].

Other degradation products of the cytosine moiety were isolated and characterized. These include 5-hydroxy -deoxycytidine 5-OHdCyd 22 and 5-hydroxy -deoxyuridine 5-OHdUrd 23 that are produced from dehydration reactions of 5,6-dihydroxy-5,6-dihydro -deoxycytidine 20 and 5,6-dihydroxy-5,6-dihydro -deoxyuridine 21respectively. MQ-photosensitized oxidation of neuberechhung also results in the formation of six minor nucleoside photoproducts, which include the two trans diastereomers of N- 2-deoxy-b-D-erythro-pentofuranosyl carbamoyl-4;5-dihydroxy-imidazolidin2-one, N1- 2-deoxy-b-D-erythro-pentofuranosyl -N4-ureidocarboxylic acid and the a and b anomers of N- 2-deoxy-D-erythro-pentosyl -biuret [32, 53].

On the other hand, the dCyd pyrimidine radical cation 15 undergoes competitive deprotonation from the exocyclic N3 group giving rise to 20 -deoxyuridine 25 by way of an aminyl radical 24, and from the C position of the sugar moiety leading to the release of cytosine [55]. The release of cytosine involves N-glycosidic bond cleavage and may be accounted for by loss of nwuberechnung anomeric proton and subsequent transformation of the C -neutral radical 26 into highly alkali-labile 2-deoxyribonolactone 27 [56].

This pathway probably involves the formation of related peroxyl radicals, loss of superoxide radical and further hydrolysis of the resulting sugar carbocation. The formation of 5-hydroxy -deoxycytidine 22 and 5-hydroxy -deoxyuridine 23 that arise from dehydration of dCyd glycols 20 and related dUrd derivatives 21, respectively, was assessed by HPLC-electrochemical detection within calf thymus DNA upon exposure to photoexcited menadione and subsequent enzymatic hydrolysis [57].

Information is also available on the main chemical reactions of base radical cations 29 of 5-methyl -deoxycytidine 5-MedCyd 28a minor DNA nucleoside that plays a major role in regulating gene expression at CpG sequences.

The main reaction involves loss of a proton from the methyl group as previously observed for Thd. Subsequently, the 2-deoxycytidylyl methyl radical 30 incorporates oxygen to give rise to the corresponding peroxyl radical, which undergoes reduction by O2.

In addition, two stable methyl oxidation products were isolated and assigned as 5 hydroxymethyl -deoxycytidine 32 and 5-formyl -deoxycytidine They likely arise from a Russell mechanism [59, 60] that involves the transient formation of tetroxides through the condensation of two peroxyl radicals. It was also shown that 5-formyl -deoxycytidine 33 is the predominant MQ-mediated photooxidation product of 5- hydroxymethyl -deoxycytidine It may be noted that competitive deprotonation of 29 at C gives rise to 2-deoxyribonolactone 27 with the concomitant release of free 5-methylcytosine as minor processes.

Interestingly, competitive hydration of 5-MedCyd radical cations 29 occurs exclusively at C-6 as inferred from labeling experiments with 18O2 36 [61].

Thus, mass spectrometry analysis of the four cis and trans diastereomers of 5-MedCyd glycols 36 showed that incorporation of 18O2 takes place exclusively at C-5 of 6-hydroxy-5,6-dihydro -deoxycytydyl radicals An interesting feature of 5-MedCyd glycols 36 is the much higher stability toward hydrolytic deamination compared to dCyd homologues 20, the cis diastereomers being more easily converted into the corresponding Thd glycols 7 than the trans forms [62].

The high selectivity of the hydration reaction was confirmed by the lack of formation of the four cis and trans diastereomers of 3- 2-deoxy-b-D-erythro-pentofuranosyl carbamoyl-4,5-dihydroxymethyloxo-imidazolidine. Fixation of O2 to the latter radical is likely to give rise to the related C-6 substituted hydroperoxide, which is able to undergo intramolecular cyclization with subsequent rearrangement of the pyrimidine ring. Various physical processes, including the direct effect of ionizing radiation [63] and bi-photonic high intensity UV lasers [64—66], together with type I photosensitizers [51, 67], are able to promote the formation of the radical cation 38 upon one-electron oxidation of the guanine moiety of DNA and related nucleosides such as 20 -deoxyguanosine dGuo The two overwhelming oxidation products of the purine moiety of dGuo 37 arising from the transformation of guanine radical cations 38 were isolated and identified as 2,2-diamino[ 2-deoxy-b-D-erythro-pentofuranosyl amino]-5 2H -oxazolone 41 and its precursor 2-amino[ 2-deoxy- Effects of Duplex Stability on Charge-Transfer Efficiency within DNA 11 Scheme 4 One-electron oxidation reactions of 20 -deoxyguanosine in aerated aqueous solutions b-D-erythro-pentofuranosyl amino]-4H-imidazolone 40 [73, 74].

The mechanism of their production Scheme 4 may be rationalized in terms of the transient formation of oxidizing guanilyl radicals 39 that arise from deprotonation of 38 [75].