Quinacrine and 9-Amino Acridine Inhibit B-Z and B-H L Form DNA Conformational Transitions

Abstract

The interaction of quinacrine and 9-amino acridine with right-handed B-form, left-handed Z-form, and left-handed protonated (H^L)-form structures of polydG-me⁵dC was investigated by circular dichroism and absorption spectral analysis. Both the compounds bind strongly to the B-form structure and convert the Z-form and H^L-form back to the bound right-handed form. Circular dichroic data revealed that the conformation at the binding site is right-handed even though adjacent regions of the polynucleotide may have left-handed conformation. The rate and extent of B-form–to–Z-form transition were decreased in the presence of these compounds. Scatchard analysis revealed that both quinacrine and 9-amino acridine bind strongly to the polynucleotide in the B-form in a noncooperative manner, in sharp contrast to the highly cooperative binding to the Z-form and H^L-form. Results indicated that the cooperative binding of these drugs with the Z-form and the H^L-forms was associated with a sequential conversion of the polynucleotide from a left-handed to a bound right-handed conformation. Experimental data enabled the calculation of the number of base pairs of Z-form (7–8 with quinacrine and 9-amino acridine) and H^L-form (4 and 25, respectively, with quinacrine and 9-amino acridine) that adopt a right-handed conformation for each bound ligand. As these compounds are known to bind preferentially to alternating guanine–cytosine sequences, which are capable of easily undergoing the B-to-Z or B-to-H^L transition, these effects may be important in understanding their biological activities.