SEQUENCE-SELECTIVE BINDING TO DNA OF CIS-BUTAMIDINE AND TRANS-BUTAMIDINE ANALOGS OF THE ANTIPNEUMOCYSTIS-CARINII PNEUMONIA DRUG PENTAMIDINE

Footprinting experiments using both DNase I and methidium propyl-EDTA Fe(ll) have been used to investigate the sequence selectivity in bindi ng to DNA of pentamidine and four butamidine analogues active against the Pneumocystis carinii pathogen, which afflicts patients with acquir ed immunodeficiency syndrome. In common with pentamidine, the butamidi ne 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. No ne of the drugs tolerates the presence of a G.C base pair within the b inding site. Consistently in the DNase I and methidium propyl-EDTA.Fe( II) footprinting experiments, the cis-isomers produce stronger footpri nts than do the trans-isomers, despite their similar hydrogen-bonding potentialities. The present experimental data support the view that th e conformation of the drug plays a determining role in the binding rea ction. Starling from the known structure of a pentamidine-oligonucleot ide complex, it is possible to rationalize the different capacities of the cis- and trans-butamidine analogues to recognize defined DNA sequ ences in terms of the radius of curvature of the molecule and the dist ance between the positively charged terminal groups. Together, these f eatures constitute critical factors favoring (cis-conformation) or ham pering (trans-conformation) the fitting of the drugs into the minor gr oove of DNA. In terms of structure-activity relationships, the AT-spec ific recognition of DNA by this series of butamidine derivatives canno t be directly correlated with their potencies against Pneumocystis car inii pneumonia.