STRUCTURES OF ACROLEIN-GUANINE ADDUCTS - A SEMIEMPIRICAL SELF-CONSISTENT-FIELD AND NUCLEAR-MAGNETIC-RESONANCE SPECTRAL STUDY

The structures and conformations of adducts formed by reaction of guan osine with several mutagenic alpha,beta-unsaturated carbonyl compounds have been investigated by semi-empirical molecular orbital calculatio ns and compared with NMR spectral results. Two cyclization processes t aking place on the pyrimidine ring of guanine leading to two sets of r egioisomers, 11-hydroxy-and 13-hydroxytetrahydropyrimidinoguanines (TH PG), were considered. Relative stabilities and geometries of all confi gurations 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 ba sed on 400-MHz H-1 NMR spectroscopy. The most stable structures for th e 11-hydroxy and 13-hydroxy THPG isomers from acrolein are predicted t o have chair-like structures for the tetrahydropyrimidine ring and axi al hydroxyl groups, as suggested by the NMR spectra of the isolated ad ducts. Of the possible isomers from guanine and crotonaldehyde, cis-11 -hydroxy-13-methyl THPG with methyl and hydroxyl groups axial is predi cted to be the most stable. The only isolated adduct is the trans-13-h ydroxy-11-methyl THPG with methyl shown to be equatorial and hydroxyl axial by H-1 NMR. This is completely consistent with the geometry pred icted 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-hydro xy isomer, the cis configuration with chlorine axial and hydroxyl quas i-axial is calculated to have the most stable geometry. In contrast, t he H-1 NMR spectrum supports a trans diaxial orientation, although the cis computed structure could also be accommodated by the spectrum. Th e 12-chloro-13-hydroxy regioisomer is unambiguously assigned as trans diaxial by PM3 calculations and H-1 NMR spectroscopy.