Boerth D W, Eder E, Hussain S, Hoffman C
Department of Chemistry, University of Massachusetts-Dartmouth, North Dartmouth, Massachusetts 02747, USA.
Chem Res Toxicol. 1998 Apr;11(4):284-94. doi: 10.1021/tx970152g.
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.
通过半经验分子轨道计算研究了鸟苷与几种诱变的α,β-不饱和羰基化合物反应形成的加合物的结构和构象，并与核磁共振光谱结果进行了比较。考虑了在鸟嘌呤的嘧啶环上发生的两个环化过程，这两个过程导致两组区域异构体，即11-羟基和13-羟基四氢嘧啶鸟嘌呤（THPG）。采用PM3、AM1和MNDO方法计算了与丙烯醛、巴豆醛和α-氯丙烯醛形成的加合物的所有构型和构象的相对稳定性和几何结构。基于400兆赫的1H核磁共振光谱，PM3结果与实验结构最相符。如分离出的加合物的核磁共振光谱所示，丙烯醛形成的11-羟基和13-羟基THPG异构体的最稳定结构预计四氢嘧啶环具有椅状结构且羟基为轴向。在鸟嘌呤和巴豆醛可能形成的异构体中，甲基和羟基为轴向的顺式-11-羟基-13-甲基THPG预计最稳定。唯一分离出的加合物是反式-13-羟基-11-甲基THPG，1H核磁共振显示甲基为平伏键，羟基为轴向。这与PM3预测的巴豆醛13-羟基区域异构体的几何结构完全一致。对于α-氯丙烯醛的加合物，两种可能的区域异构体中的每一种都有一种立体异构体占主导。对于12-氯-11-羟基异构体，氯为轴向且羟基为准轴向的顺式构型计算得出具有最稳定的几何结构。相比之下，1H核磁共振光谱支持反式双轴向取向，尽管计算出的顺式结构也能与光谱相符。通过PM3计算和1H核磁共振光谱，明确将12-氯-13-羟基区域异构体指定为反式双轴向。
