Azapsoralens-DNA interactions: crystal structure characterization of furan-side monoadduct and computer-aided studies

In this paper a theoretical study, concerning molecular mechanics optimised structures, obtained by quantum mechanics as well as molecular mechanics calculations was carried out with the aim of correlating the theoretical model of the interactions between azapsoralens and DNA with the data experimentally obtained. The theoretical model suggests that both furan-side and pyrone-side double bonds may be involved in the cycloaddition with pyrimidines (although the cycloaddition at the level of furan is preferred), and is in line with the capacity of these compounds to form inter-strand cross-links. Moreover, concerning the theoretical intercalation model calculations on 3,4,4',5'-tetramethylazapsoralen intercalated inside a polynucleotide, they suggest a cis-syn arrangement between furan-side of the intercalated ligand and the above situated thymine, with which, under light activation, a cycloadduct may take place, having a cis-syn steric arrangement. Also this datum is in agreement with the cis-syn regio and stereochemistry of the isolated 4,4',5'-trimethylazapsoralen-thymine cycloadduct. Finally, from theoretical data, the role of nitrogen seems not important: in fact only small differences were found with the corresponding methylpsoralens so that the small differences observed may be mainly attributed to steric rather than to electronic effects. In general a good correlation between the theoretical model and the experimental data was observed.