Structures of acrolein-guanine adducts: a semi-empirical self-consistent field and nuclear magnetic resonance spectral study.
The structures and conformations of adducts formed by reaction of guanosine with several mutagenic alpha,beta-unsaturated carbonyl compounds have been investigated by semi-empirical molecular orbital calculations and compared with NMR spectral results. Two cyclization processes taking place on the pyrimidine ring of guanine leading to two sets of regioisomers, 11-hydroxy- and 13-hydroxytetrahydropyrimidinoguanines (THPG), were considered. Relative stabilities and geometries of all configurations and conformations of adducts with acrolein, crotonaldehyde, and alpha-chloroacrolein were calculated by PM3, AM1, and MNDO methods. PM3 results were the most compatible with experimental structures based on 400-MHz 1H NMR spectroscopy. The most stable structures for the 11-hydroxy and 13-hydroxy THPG isomers from acrolein are predicted to have chair-like structures for the tetrahydropyrimidine ring and axial hydroxyl groups, as suggested by the NMR spectra of the isolated adducts. Of the possible isomers from guanine and crotonaldehyde, cis-11-hydroxy-13-methyl THPG with methyl and hydroxyl groups axial is predicted to be the most stable. The only isolated adduct is the trans-13-hydroxy-11-methyl THPG with methyl shown to be equatorial and hydroxyl axial by 1H NMR. This is completely consistent with the geometry predicted by PM3 for the 13-hydroxy regioisomer of crotonaldehyde. In the case of adducts of alpha-chloroacrolein, one stereoisomer predominates for each of the two possible regioisomers. For the 12-chloro-11-hydroxy isomer, the cis configuration with chlorine axial and hydroxyl quasi-axial is calculated to have the most stable geometry. In contrast, the 1H NMR spectrum supports a trans diaxial orientation, although the cis computed structure could also be accommodated by the spectrum. The 12-chloro-13-hydroxy regioisomer is unambiguously assigned as trans diaxial by PM3 calculations and 1H NMR spectroscopy.
Boerth
D W
DW
Department of Chemistry, University of Massachusetts-Dartmouth, North Dartmouth, Massachusetts 02747, USA.
Eder
E
E
Hussain
S
S
Hoffman
C
C
D000171:Acrolein / Q000031:analogs & derivatives / Q000737:chemistry*; D000447:Aldehydes / Q000737:chemistry; D018736:DNA Adducts / Q000737:chemistry*; D006147:Guanine / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D009153:Mutagens / Q000737:chemistry*
D000447:Aldehydes; D018736:DNA Adducts; D009153:Mutagens; D006147:Guanine; C028406:2-chloroacrolein; D000171:Acrolein; C012796:2-butenal