%0 Journal Article
%T Incorporation of 3-Aminobenzanthrone into 2¡ä-Deoxyoligonucleotides and Its Impact on Duplex Stability
%A Mark Lukin
%A Tanya Zaliznyak
%A Francis Johnson
%A Carlos R. de los Santos
%J Journal of Nucleic Acids
%D 2011
%I Hindawi Publishing Corporation
%R 10.4061/2011/521035
%X 3-Nitrobenzanthrone (3NBA), an environmental pollutant and potent mutagen, causes DNA damage via the reaction of its metabolically activated form with the exocyclic amino groups of purines and the C-8 position of guanine. The present work describes a synthetic approach to the preparation of oligomeric 2¡ä-deoxyribonucleotides containing a 2-(2¡ä-deoxyguanosin-N2-yl)-3-aminobenzanthrone moiety, one of the major DNA adducts found in tissues of living organisms exposed to 3NBA. The NMR spectra indicate that the damaged oligodeoxyribonucleotide is capable of forming a regular double helical structure with the polyaromatic moiety assuming a single conformation at room temperature; the spectra suggest that the 3ABA moiety resides in the duplex minor groove pointing toward the 5¡ä-end of the modified strand. Thermodynamic studies show that the dG(N2)-3ABA lesion has a stabilizing effect on the damaged duplex, a fact that correlates well with the long persistence of this damage in living organisms. 1. Introduction Nitroarenes are widespread environmental pollutants found in cigarette smoke, coal fly ash, exhausts from diesel and gasoline engines, and air particulate matter [1]. 3-Nitrobenzanthrone (3NBA, 3-nitro-7H-benz[de]anthracen-7-one), a member of this class of compounds, is one of the most potent bacterial mutagens known to date [2] and exhibits strong mutagenic activity in mammalian cells [3]. Human fibroblasts exposed to N-acetoxy-3-aminobenzanthrone, an active metabolite of 3NBA, show predominance of base substitution mutations mainly G ¡ú T transversions followed by G ¡ú A and A ¡ú G substitutions [4]. Transgenic mice treated with 3NBA exhibit increased mutation frequency in liver, colon, bladder, and bone marrow, with G ¡ú T transversions dominating this effect [5, 6]. Analysis of 3NBA-induced mutations in mouse fibroblasts harboring a functional copy of the human p53 gene also reveals a preponderance of G ¡ú T transversions, followed by adenine base substitutions [7]. In addition to mutations, 3NBA causes DNA double-strand breaks and induces the formation of micronuclei in human cell lines [8, 9]. Female F344 rats treated with 3NBA by intratracheal instillation show acute and subacute changes in their lungs just few weeks after treatment and develop squamous cell lung tumors within 9 to 12 months, depending on the amount of 3NBA administered [10]. Some epidemiological evidence links environmental 3NBA exposure to lung cancer in humans [11, 12]. Like other environmental nitroarenes, 3NBA undergoes metabolic transformation to reactive electrophilic
%U http://www.hindawi.com/journals/jna/2011/521035/