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Molecular Pharmacology

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Abstract

Sequence-selective binding to DNA of cis- and trans- butamidine analogues of the anti-Pneumocystis carinii pneumonia drug pentamidine.

C Bailly, I O Donkor, D Gentle, M Thornalley and M J Waring
Molecular Pharmacology August 1994, 46 (2) 313-322;
C Bailly
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I O Donkor
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D Gentle
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M Thornalley
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M J Waring
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Abstract

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.

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Molecular Pharmacology
Vol. 46, Issue 2
1 Aug 1994
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Abstract

Sequence-selective binding to DNA of cis- and trans- butamidine analogues of the anti-Pneumocystis carinii pneumonia drug pentamidine.

C Bailly, I O Donkor, D Gentle, M Thornalley and M J Waring
Molecular Pharmacology August 1, 1994, 46 (2) 313-322;

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Abstract

Sequence-selective binding to DNA of cis- and trans- butamidine analogues of the anti-Pneumocystis carinii pneumonia drug pentamidine.

C Bailly, I O Donkor, D Gentle, M Thornalley and M J Waring
Molecular Pharmacology August 1, 1994, 46 (2) 313-322;
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