Sequence-selective binding to DNA of bis(amidinophenoxy)alkanes related to propamidine and pentamidine.
The DNA sequences targeted by a complete homologous series of aromatic diamidines have been determined at single-nucleotide resolution via protection from cutting by the endonucleases DNase I, DNase II and micrococcal nuclease. Propamidine, pentamidine and to a lesser extent hexamidine bind selectively to nucleotide sequences composed of at least four consecutive A-T base pairs. In contrast, the binding to DNA of butamidine, heptamidine, octamidine and nonamidine is poorly sequence-selective. Sequences composed of only three consecutive A-T base pairs do not afford a potential binding site for propamidine or the longer homologues, and none of the drugs tolerate the presence of a G-C base pair within the binding site. Experiments with DNA molecules containing inosine in place of guanosine and 2,6-diaminopurine in place of adenine reveal that the lack of binding of propamidine to GC-containing sites is attributable to an obstructive effect of the exocyclic 2-amino group of guanosine. The present data support the view that the local conformation of the double helix (in particular the width of the minor groove) plays a dominant role in the binding reaction and that the capacity of diamidines to recognize AT-rich sequences selectively varies considerably depending on the length of the alkyl chain. The evidence indicates that binding to AT-tracts in DNA must play a role in the biological activity of these diamidines, but there is no simple correlation between binding and pharmacological efficacy.
Bailly
C
C
INSERM U124, Institut de Recherches sur le Cancer, Place de Verdun, 59045, Lille, France.
Perrine
D
D
Lancelot
J C
JC
Saturnino
C
C
Robba
M
M
Waring
M J
MJ
D000473:Alkanes / Q000737:chemistry / Q000378:metabolism*; D001482:Base Composition; D001483:Base Sequence; D001550:Benzamidines / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D018983:DNA Footprinting; D004926:Escherichia coli; D008969:Molecular Sequence Data; D010419:Pentamidine / Q000378:metabolism*; D015183:Restriction Mapping; D013329:Structure-Activity Relationship
D000473:Alkanes; D001550:Benzamidines; D010419:Pentamidine; D004247:DNA; C005555:propamidine