Document 0234
 DOCN  M94A0234
 TI    Sequence-selective binding to DNA of cis- and trans- butamidine
       analogues of the anti-Pneumocystis carinii pneumonia drug pentamidine.
 DT    9412
 AU    Bailly C; Donkor IO; Gentle D; Thornalley M; Waring MJ; Department of
       Pharmacology, University of Cambridge, UK.
 SO    Mol Pharmacol. 1994 Aug;46(2):313-22. Unique Identifier : AIDSLINE
       MED/94359494
 AB    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.
 DE    Base Sequence  Binding Sites  DNA/*METABOLISM  Human  Molecular Sequence
       Data  Pentamidine/*ANALOGS & DERIVATIVES/CHEMISTRY/*METABOLISM/
       PHARMACOLOGY  Pneumocystis carinii/*DRUG EFFECTS  Structure-Activity
       Relationship  Support, Non-U.S. Gov't  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).