Footprinting experiments using both
DNase I and methidium propyl-
EDTA.Fe(II) have been used to investigate the sequence selectivity in binding to
DNA of
pentamidine and four
butamidine analogues active against the Pneumocystis carinii pathogen, which afflicts patients with
acquired immunodeficiency syndrome. In common with
pentamidine, the
butamidine drugs, which contain cis- or trans-1,4-but-2-ene linkers and either bis(amidine) or bis(
imidazolidine) terminal groups, bind selectively to DNA sequences composed of at least 4 consecutive A.T base pairs. None of the drugs tolerates the presence of a G.C base pair within the binding site. Consistently in the
DNase I and methidium propyl-
EDTA.Fe(II) footprinting experiments, the cis-isomers produce stronger footprints than do the trans-isomers, despite their similar hydrogen-bonding potentialities. The present experimental data support the view that the conformation of the
drug plays a determining role in the binding reaction. Starting from the known structure of a
pentamidine-
oligonucleotide complex, it is possible to rationalize the different capacities of the cis- and trans-
butamidine analogues to recognize defined DNA sequences in terms of the radius of curvature of the molecule and the distance between the positively charged terminal groups. Together, these features constitute critical factors favoring (cis-conformation) or hampering (trans-conformation) the fitting of the drugs into the minor groove of
DNA. In terms of structure-activity relationships, the AT-specific recognition of
DNA by this series of
butamidine derivatives cannot be directly correlated with their potencies against
Pneumocystis carinii pneumonia.