Structures of Exocyclic R,R- and S,S-N super(6),N super(6)-(2,3-Dihydroxy butan-1,4-diyl)-2'-Deoxyadenosine Adducts Induced by 1,2,3,4-Diepoxybutane

• Published in: Chemical research in toxicology Vol. 27; no. 5; pp. 805 - 817-805-817
• Main Authors: Kowal, Ewa A, Seneviratne, Uthpala, Wickramaratne, Susith, Doherty, Kathleen E, Cao, Xiangkun, Tretyakova, Natalia, Stone, Michael P
• Format: Journal Article
• Language: English
• Published: 19.05.2014
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/tx400472p

1,3-Butadiene (BD) is an industrial and environmental chemical present in urban air and cigarette smoke, and is classified as a human carcinogen. It is oxidized by cytochrome P450 to form 1,2,3,4-diepoxybutane (DEB); DEB bis-alkylates the N super(6) position of adenine in DNA. Two enantiomers of bis-N super(6)-dA adducts of DEB have been identified: R,R-N super(6),N super(6)-(2,3-di hydroxybutan-1,4-diyl)-2'-deoxyadenosine (R,R-DHB-dA), and S,S-N super(6),N super(6)-(2,3-di hydroxybutan-1,4-diyl)-2'-deoxyadenosine (S,S-DHB-dA) [Seneviratne, U., Antsypovich, S., Dorr, D. Q., Dissanayake, T., Kotapati, S., and Tretyakova, N. (2010) Chem. Res. Toxicol.23, 1556-1567]. Herein, the R,R-DHB-dA and S,S-DHB-dA adducts have been incorporated into the 5'-d(C super(1)G super(2)G super(3)A super(4)C super(5)X super(6)A super(7)G super(8)A super(9)A super( 10)G super(11))-3':5'-d(C super(12)T super(13 )T super(14)C super(15)T super(16)T super(17)G super( 18)T super(19)C super(20)C super(21)G super(22))-3' duplex [X super(6) = R,R-DHB-dA (R super(6)) or S,S-DHB-dA (S super(6))]. The structures of the duplexes were determined by molecular dynamics calculations, which were restrained by experimental distances obtained from NMR data. Both the R,R- and S,S-DHB-dA adducts are positioned in the major groove of DNA. In both instances, the bulky 3,4-dihydroxypyrrolidine rings are accommodated by an out-of-plane rotation about the C6-N super(6) bond of the bis-alkylated adenine. In both instances, the directionality of the dihydroxypyrrolidine ring is evidenced by the pattern of NOEs between the 3,4-dihydroxypyrrolidine protons and DNA. Also in both instances, the anti conformation of the glycosyl bond is maintained, which combined with the out-of-plane rotation about the C6-N super(6) bond, allows the complementary thymine, T super(17), to remain stacked within the duplex, and form one hydrogen bond with the modified base, between the imine nitrogen of the modified base and the T super(17) N3H imino proton. The loss of the second Watson-Crick hydrogen bonding interaction at the lesion sites correlates with the lower thermal stabilities of the R,R- and S,S-DHB-dA duplexes, as compared to the corresponding unmodified duplex. The reduced base stacking at the adduct sites may also contribute to the thermal instability.