The impact of the nucleoside oxidation on the susceptibility to chemical carcinogens studied by first principle and semiempirical quantum chemistry methods Piotr Cysewski Department of Physical Chemistry, Collegium Medicum, Nicolaus Copernicus University, Kurpin ´skiego 5, 85-950 Bydgoszcz, Poland Department of General Chemistry, University of Technology and Life Sciences Bydgoszcz, Seminaryjna 3, 85-326 Bydgoszcz, Poland article info Article history: Received 17 January 2008 Received in revised form 5 May 2008 Accepted 8 May 2008 Available online 15 May 2008 Keywords: Ionization potential Hydroxyl radical Chemical carcinogen 8-Oxoguanosine abstract The B3LYP/aug-cc-pvdz and AM1-CI quantum chemistry calculations were used for estimation of adia- batic and vertical ionization potential values of 22 hydroxyl radical modified purine and pyrimidine model nucleosides. Most of studied derivatives are characterized by higher values of IP compared to canonical guanosine, which is known to be the main target for oxidizing agents and chemical carcinogens in cellular DNA. However, three derivatives, namely fapy-guanosine, 8-oxoguanosine and 2-oxoadeno- sine are characterized by lower IP values than canonical guanosine. Thus, 6,8-diketo- and 6-enol-8- keto-tautomer of 8-oxoguanosine, 6-enol- and 6-keto tautomers of fapy-guanosine as well as 2-keto form of 2-oxoadenosine may be potential hot spot centers for chemical carcinogens. The IEFPCM calculations confirm above conclusion even in the polar environment. Ó 2008 Elsevier B.V. All rights reserved. 1. Introduction Chemical carcinogens itself or its metabolic products are elec- trophilic reactants, which exert their biological effects by covalent interactions with cellular macromolecules as DNA, RNA or proteins [1]. Since activation of oncogenes or inactivation of tumor sup- presser genes is a core of the transformation of a normal cell into a tumorigenic ones, most of carcinogens posses also the mutagenic properties [2,3]. The process of carcinogenesis is thought as multi- stage phenomena finally leading to formation of a tumor [3]. It was proposed [4–7] that in the first stage a conversion of the pre-car- cinogens into electrophilic reagents is followed by the modification of the DNA as a consequence of the electron donation from HOMO located on DNA site to LUMO of carcinogen. A general classification between carcinogenic and noncarcinogenic species can be then ob- tained from the LUMO energy analysis [6]. On the other hand the most probable target for carcinogen attack may be identified from high energies of HOMO [7]. Since the attack of carcinogen results in electron transfer and formation of cationic form at DNA target site there are thee alternative quantities, which may be taken into con- sideration, namely ionization potential (IP) estimated from the Koopmans approximation (IP = -HOMO), vertical IP calculated as the energy (or Gibbs free energy) difference between cationic and neutral form without relaxation of the geometry and adiabatic IP, which includes the geometry relaxation after ionization. One of the extremely important carcinogens are reactive oxygen forms [8] leading to variety of oxidized species of canonical nucleic acid bases [9]. There are strong experimental evidences that guanine is the most probable site for holes trapping [10–13] since it has the smallest value of IP among all purines and pyrimidines [13– 15]. Moreover, since GG and GGG stacked guanine sequences have lower ionization potentials than single guanine [16] such se- quences are even more probable sites for undergoing the oxidation process. Thus, mutations occur predominantly at G clusters as a re- sult of long-distance hole transport through DNA from single guan- ine to GG sequences. This is of special importance since several hot spot codons of tumor suppressor genes as well as human ras proto- oncogenes are rich in GG sequences [17]. The ionization potentials are also important for understanding of the long-distance charge transport in DNA [13]. From this perspective the ionization proper- ties of DNA bases were extensively studied both by experimental [14,15,18–21] and by different theoretical methods [22–26]. It is commonly accepted that reactive oxygen forms may ex- change genetic code by formation of many oxidized derivatives [1,8,9]. The nucleic acid bases were proven to be one of major tar- gets for ROF. This has far biochemical consequences as bases deg- radation, cross-linking or different lesions formation. More than 20 stable nucleotide derivatives were identified in the cellular DNA [9]. Among them the most known is 8-oxoguanine (GA), often utilized as a biomarker of free-radical related diseases [9]. Although the concentration of the modified bases in cellular DNA is much less compared to canonical one, they are responsible for many defective activities as miscoding, misreading, cytotoxicity, replication blocking and others [9]. Thus, it seems to be interesting 0166-1280/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.theochem.2008.05.004 E-mail address: piotr.cysewski@cm.umk.pl Journal of Molecular Structure: THEOCHEM 863 (2008) 16–21 Contents lists available at ScienceDirect Journal of Molecular Structure: THEOCHEM journal homepage: www.elsevier.com/locate/theochem