Absolute configurations and stability of cyclic guanosine mono-adducts with glyoxal and methylglyoxal

Abstract

Glyoxal and methylglyoxal are two endogenous and mutagenic 1,2-dicarbonyl compounds, which can readily form adducts with guanosine. The molecular structures of cyclic guanosine-glyoxal (G-g) and guanosine-methylglyoxal (G-mg) mono-adducts have been extensively studied before. However, diastereoisomers of these adducts have not yet been studied in detail. In this work, one pair of G-g and two pairs of G-mg diastereoisomers were baseline separated by reverse phase HPLC, whose structures were identified as the previously reported cyclic forms, and their absolute configurations were determined by circular dichroism, the octant rule, and molecular modeling. According to the HPLC elution order, configurations of two G-g (as well as trans G-mg) were (6R,7R) and (6S,7S), respectively. Meanwhile, the stability of each isomer in neutral solution was also investigated, which revealed the stability order G-g > cis G-mg > trans G-mg and also indicated distinct transformation processes for different G-mg configurations. Trans G-mg only racemized between each other, while cis G-mg transformed to both cis and trans forms. Different intermediates in the racemization processes were proposed to explain the observations. These results may shed light on further understanding the roles of these two small molecules in mutagenesis.