A theoretical study of the intercalative binding of the anti-tumour drug anthrapyrazole to double-stranded oligonucleotides.

Theoretical computations have been performed on the intercalative binding of anthrapyrazole to the double-stranded tetranucleotides d(GCGC)2 and d(ATAT)2, intercalation taking place in the central pyrimidine-(3',5')-purine sequences, with an unwinding angle of 29 degrees. The complex is principally stabilized by hydrogen-bonds of the two side chains with the ionic oxygens of the two central phosphates. In marked contrast with the corresponding complexes of the related compound mitoxantrone, the N7 atoms of the two central purines do not participate in hydrogen-bonding interactions with the dimethylamino fragments of the side chains. Side chain A of the anthrapyrazole, which is on the imino nitrogen side, is located farther away from the core of the major groove, closer to the phosphate backbone. Compared to the mitoxantrone complexes, there is a considerable decrease in the difference of interaction energy between the d(GCGC)2 and the d(ATAT)2 complexes. This is in line with the experimental results indicating that, compared to mitoxantrone, anthrapyrazole manifests little or no GC sequence selectivity.