Oxidative Damage of Thymidines by the Atmospheric Free-Radical Oxidant NO3 •
Uta Wille A B and Catrin Goeschen AA ARC Centre of Excellence for Free Radical Chemistry and Biotechnology, School of Chemistry and BIO21 Molecular Science and Biotechnology Institute, The University of Melbourne, 30 Flemington Road, Parkville, Vic. 3010, Australia.
B Corresponding author. Email: uwille@unimelb.edu.au
Uta Wille graduated from her Ph.D. in Science at the University of Kiel, Germany, in 1993. Her Ph.D. thesis was performed in the area of Atmospheric Chemistry. After this, she changed her research directions when she was offered a position for a Habilitation in Organic Chemistry at the same institution, which was completed in 1999. In 1997/98 she undertook a Postdoctoral Fellowship with Professor Bernd Giese at the University of Basel, Switzerland. In 1999, she was appointed as Privatdozent at the University of Kiel and was invited in 2000 as a Visiting Fellow in the School of Chemistry at The University of Melbourne. In January 2003, Uta moved permanently to Australia, where she was appointed as a Lecturer in the School of Chemistry at The University of Melbourne, promoted to Senior Lecturer in 2006 and Associate Professor and Reader in 2011. Uta Wille is a Chief Investigator in the ARC Centre of Excellence for Free Radical Chemistry and Biotechnology. Her research program targets the chemistry of reactive intermediates by merging radicals of atmospheric importance with organic and bio-organic chemistry. |
Australian Journal of Chemistry 64(6) 833-842 https://doi.org/10.1071/CH11102
Submitted: 7 March 2011 Accepted: 31 March 2011 Published: 27 June 2011
Abstract
Analysis of the products formed in the reaction of nitrate radicals, NO3 •, with the N- and O-methylated and acetylated thymidines 1a and 1b revealed, for the first time, insight regarding how this important atmospheric free-radical oxidant can cause irreversible damage to DNA building blocks. Mechanistic studies indicated that the initial reaction step likely proceeds via NO3 • induced electron transfer at the pyrimidine ring, followed by deprotonation of the methyl group at C5. The oxidation ultimately leads to formation of nitrates 2, aldehydes 4 and, in the case of high [NO3 •], also to carboxylic acids 5. In addition to this, through a very minor pathway, loss of the methyl group at C5 also occurred to give the respective 2′-deoxyuridines 6. The nitrates 2 are highly labile compounds that undergo rapid hydrolysis during work-up and purification of the reaction mixtures, which could lead to serious misinterpretation of the experimental findings and reaction mechanism. Products resulting from NO3 • addition to the C5=C6 double bond in the pyrimidine ring were not observed. Also, no reaction of NO3 • with the 2′-deoxyribose moiety was detected.
References
[1] C. J. Burrows, J. G. Muller, Chem. Rev. 1998, 98, 1109.| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1cXis12htrY%3D&md5=c867877fd118cb4742256459f73e6e36CAS | 11848927PubMed |
[2] W. K. Pogozelski, T. D. Tullius, Chem. Rev. 1998, 98, 1089.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1cXis12gtL8%3D&md5=7b42283b23a80efc6208178f07c1b370CAS | 11848926PubMed |
[3] S. Steenken, Chem. Rev. 1989, 89, 503.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaL1MXitVyms7w%3D&md5=2b840c5c687c9fdfacb6dc516b7752b7CAS |
[4] D. Schulte-Frohlinde, K. Hildenbrandt, Electron spin resonance studies of the reactions of OH• and SO4 •– radicals with DNA, polynucleotides and single base model compounds, in Free Radicals in Synthesis and Biology 1989, p. 335 (Ed. F. Minisci) (NATO ASI Series, C260, Kluwer: Dordrecht).
[5] R. Lomoth, S. Naumov, O. Brede, J. Phys. Chem. A 1999, 103, 6571.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1MXlt1Wjsr8%3D&md5=bae7d214093878bc9bb6d7d8cf6d3169CAS |
[6] D. K. Hazra, S. Steenken, J. Am. Chem. Soc. 1983, 105, 4380.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaL3sXkt1arsbs%3D&md5=18f6ed315f53ddb48e7b48d08182856eCAS |
[7] W. F. Ho, B. C. Gilbert, M. J. Davies, J. Chem. Soc., Perkin Trans. 2 1997, 2525.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1cXhvVGgtQ%3D%3D&md5=7340601fab3ec8d214ff12e0fb36bcd0CAS |
[8] W. F. Ho, B. C. Gilbert, M. J. Davies, J. Chem. Soc., Perkin Trans. 2 1997, 2533.
| Crossref | GoogleScholarGoogle Scholar |
[9] D. J. Deeble, M. N. Schuchmann, S. Steenken, C. von Sonntag, J. Phys. Chem. 1990, 94, 8186.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK3cXlvFWjtrs%3D&md5=17ad2b782118ece4c2d8da4502f520b3CAS |
[10] K. Chabita, P. C. Mandal, S. N. Bhattacharyya, Bull. Chem. Soc. Jpn. 1994, 67, 2751.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2cXmslGgsbc%3D&md5=630e72184152ba9767b52668a41bb230CAS |
[11] M. Faraggi, F. Broitman, J. B. Trent, M. H. Klapper, J. Phys. Chem. 1996, 100, 14751.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK28Xksl2gtr0%3D&md5=05b4b260e59f8a563d812408e469a490CAS |
[12] M. Martini, J. Termini, Chem. Res. Toxicol. 1997, 10, 234.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2sXhsVSktro%3D&md5=85cf45869574d875f245ec386d69aff2CAS | 9049436PubMed |
[13] T. Itahara, Y. Fujii, M. Tada, J. Org. Chem. 1988, 53, 3421.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaL1MXhsFCjsrY%3D&md5=1ccb29fa68e4b6a7a145f2d92e984010CAS |
[14] J. R. Wagner, J. Cadet, G. J. Fisher, Photochem. Photobiol. 1984, 40, 589.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaL2MXnsVyjtA%3D%3D&md5=cd7c5c646067d640fe922ee03722ef25CAS |
[15] C. Lagercrantz, J. Am. Chem. Soc. 1973, 95, 220.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaE3sXmvVeguw%3D%3D&md5=45d264c0611599e9eccd8792c01f380cCAS | 4345549PubMed |
[16] P. Neta, Radiat. Res. 1972, 49, 1.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaE38XlvFGmtw%3D%3D&md5=34a64b3741016d31b567d290b1b83c85CAS | 4333051PubMed |
[17] S. Fujita, S. Steenken, J. Am. Chem. Soc. 1981, 103, 2540.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaL3MXktVKisrw%3D&md5=ddea03896b26fbab7a11121d00019909CAS |
[18] J. Cadet, R. Téoule, Bull. Soc. Chim. Fr. 1975, 891.
| 1:CAS:528:DyaE28XisVegtQ%3D%3D&md5=a36c050e726ebf0de3a7bbf149c2aaa7CAS |
[19] R. P. Wayne, I. Barnes, P. Biggs, J. P. Burrows, C. E. Canosa-Mas, J. Hjorth, G. Le Bras, G. K. Moortgat, D. Perner, G. Restelli, H. Sidebottom, Atmos. Environ. 1991, A25.
[20] R. Atkinson, J. Phys. Chem. Ref. Data 1991, 20, 459.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK3MXltlGitLo%3D&md5=4f1b875b2b92c77fbfad5cc2c5f52d3cCAS |
[21] R. P. Wayne, Experimental Study of the Nitrate Radical, in N-Centered Radicals 1998, p. 207 (John Wiley & Sons: Chichester).
[22] O. Ito, Reactions of NO3 Radicals in Organic Solvents, in N-Centered Radicals 1998, p. 345 (John Wiley & Sons: Chichester).
[23] D. C. E. Sigmund, U. Wille, Chem. Commun. 2008, 2121.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXltFyntb8%3D&md5=1e9a48436c14d4007205e7efc562ab4bCAS |
[24] C. Goeschen, N. Wibowo, J. M. White, U. Wille, Org. Biomol. Chem. 2011, 3380.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXks12is70%3D&md5=d44b4a38d700b51146454bd596ae6371CAS | 21412525PubMed |
[25] O. Krüger, U. Wille, Org. Lett. 2001, 3, 1455.
| Crossref | GoogleScholarGoogle Scholar | 11388840PubMed |
[26] U. Wille, Oxidative Splitting of Pyrimidine Cyclobutane Dimers, in Highlights in Bioorganic Chemistry: Methods and Applications 2003, p. 352 (Eds C. Schmuck, H. Wennemers) (Wiley-VCH: Weinheim).
[27] L. Dogliotti, E. Hayon, J. Phys. Chem. 1967, 71, 3802.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaF1cXisFequg%3D%3D&md5=c404dc304c07c919d6a0c424bee6dd58CAS |
[28] E. Baciocchi, T. Del Giacco, S. M. Murgia, G. V. Sebastiani, J. Chem. Soc. Chem. Commun. 1987, 1246.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaL1cXhsV2rtrY%3D&md5=a7e47d542538f3eecabafc2ab2755c9aCAS |
[29] Because of the different UV absorptions of the various products, the relative peak area in the HPLC chromatograms recorded at λ 260 nm cannot be used as a measure to determine absolute yields in dependence of reaction time. The data shown in Figure 2 only provide a qualitative, but nevertheless highly useful insight into formation and consumption of the reaction products.
[30] P. Neta, R. E. Huie, J. Phys. Chem. 1986, 90, 4644.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaL28Xlt1WlsrY%3D&md5=5e3daaefd7ceb44ec67da0bb0a8f9e48CAS |
[31] L. Eberson, Adv. Phys. Org. Chem. 1982, 18, 79.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaL38XkvFWhsLk%3D&md5=46ffb857a5a23f6aba865a3817167220CAS |
[32] O. Ito, S. Akiho, M. Iino, J. Org. Chem. 1989, 54, 2436.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaL1MXitFajtr0%3D&md5=90ce89f6e66fad26d686293965b764aaCAS |
[33] V. Nair, A. Deepthi, Chem. Rev. 2007, 107, 1862.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2sXktFCqsr8%3D&md5=ef9b204a31972a0fdd9863e3ccf8aa55CAS | 17432919PubMed |
[34] J. J. Ritter, P. P. Minieri, J. Am. Chem. Soc. 1948, 70, 4045.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaH1MXhtVyjsw%3D%3D&md5=e7a6752bddb87a16000eca4a2a18c9bdCAS | 18105932PubMed |
[35] L. I. Krimen, D. J. Cota, Org. React. 1969, 17, 213.
| 1:CAS:528:DyaF1MXksVyrur8%3D&md5=f8f0c20eddc055c2c770d4c59b7e9e3cCAS |
[36] T. Shono, Y. Yoshinari, K. Takigawa, H. Maekawa, M. Ishifune, S. Kashimura, Chem. Lett. 1994, 23, 1045.
| Crossref | GoogleScholarGoogle Scholar |
[37] U. Wille, J. Phys. Org. Chem. 2011, in press.
[38] J. A. Howard, K. U. Ingold, J. Am. Chem. Soc. 1968, 90, 1056.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaF1cXktlGjtb8%3D&md5=581ef4928f8ffb9984eb741c9a2cf25aCAS |
[39] B. D’Anna, Ø. Andresen, Z. Gefen, C. J. Nielsen, Phys. Chem. Chem. Phys. 2001, 3, 3057.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXlt1ynsrs%3D&md5=a2fe30fbac82e93c787abd7a276a0ae8CAS |
[40] N. J. Turro, I. R. Gould, B. H. Baretz, J. Phys. Chem. 1983, 87, 531.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaL3sXovVKmug%3D%3D&md5=baa66776789640b04ab7e42887d6c70cCAS |
[41] A. S. Anderson, J. T. Hwang, M. M. Greenberg, J. Org. Chem. 2000, 65, 4648.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3cXksVejsbw%3D&md5=c83ff6243e9e894eaff530e2c2e817a7CAS | 10959870PubMed |
[42] S. Bjelland, L. Eide, R. W. Time, R. Stote, I. Eftedal, G. Volden, E. Seeberg, Biochemistry 1995, 34, 14758.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2MXovVyitr4%3D&md5=1451f75546bb46108c93a1634ff0f167CAS | 7578084PubMed |
[43] K. Hirota, Y. Katade, K. Shimada, Y. Maki, J. Org. Chem. 1985, 50, 1512.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaL2MXhvVCqt7g%3D&md5=6934fff80bdbee2291e5d31b40676a28CAS |
[44] M. Tsunoda, T. Sakaue, S. Naito, T. Sunami, N. Karino, Y. Ueno, A. Matsuda, A. Takénaka, Nucleic Acids Res. Suppl. 2001, 279.
| 1:STN:280:DC%2BD3szgvV2isg%3D%3D&md5=e100b7aaecb6cdfec93d26cae24f2126CAS | 12836373PubMed |
[45] J. S. W. Holtz, I. K. Lednev, S. A. Asher, Biopolymers 2000, 57, 55.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3cXisVahsL0%3D&md5=9a3151fa8c78910957e465a17efc3f84CAS | 10766956PubMed |
[46] G. A. Poskrebyshev, P. Neta, R. E. Huie, J. Geophys. Res. 2001, 106, 4995.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXltlSitbo%3D&md5=1915113ddb9fec4172dde4461dfd1701CAS |
[47] W. F. Bryant, P. D. Klein, Anal. Biochem. 1975, 65, 73.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaE2MXksFykt7s%3D&md5=83ed2b1c10ee5ffa71ca42495f2bf56dCAS | 1130702PubMed |
[48] A. M. Michelson, A. R. Todd, J. Chem. Soc. 1955, 816.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaG28Xos1ei&md5=535b9cb1f84bb2014cbf50ceedefd3ccCAS |
[49] A. P. De Leenheer, C. F. Gelijkens, Anal. Chem. 1976, 48, 2203.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaE28Xlslelt7c%3D&md5=6edd3a228026a3c6abfe8a6f7028c37dCAS | 999003PubMed |
