Design of composite drug molecules: mutual effects on binding to DNA of an intercalator, amsacrine, and a minor groove binder, netropsin.
A variety of spectroscopic and biochemical techniques have been employed to investigate the extent to which binding to DNA of an intercalator (amsacrine or its 4-carboxamide derivative SN16713) affects the binding of netropsin, a minor groove-targeted ligand, and vice versa. In general, rather little mutual interference has been found and the binding of one drug is compatible with binding of the other. The anilinoacridines exert little or no effect on the positioning of netropsin in the minor groove, judged by circular dichroism spectroscopy and electric linear dichroism, whereas netropsin has a perceptible effect on the intercalative binding of amsacrine, but not that of SN16713. Neither acridine drug prevents the netropsin-induced Z-->B structure reversion observed with poly(dG-dC).poly(dG-dC) in buffer containing 60% ethanol. The kinetics of dissociation of any one drug from its DNA complex are affected little, if at all, by the simultaneous presence of the other. Footprinting experiments with the several drugs singly or in combination reveal a certain amount of mutual interference, but the selective recognition of AT-rich sequences by netropsin tends to dominate the recognition pattern and is largely maintained in the presence of a considerable excess of amsacrine or its 4-carboxamide derivative.
Bourdouxhe
C
C
Laboratoire de Chimie Macromoléculaire et Chimie Physique, Université de Liège, Belgium.
Colson
P
P
Houssier
C
C
Hénichart
J P
JP
Waring
M J
MJ
Denny
W A
WA
Bailly
C
C
D000677:Amsacrine / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002417:Cattle; D002942:Circular Dichroism; D004247:DNA / Q000378:metabolism*; D015195:Drug Design; D007364:Intercalating Agents / Q000378:metabolism*; D008969:Molecular Sequence Data; D009429:Netropsin / Q000378:metabolism*; D009838:Oligodeoxyribonucleotides; D013057:Spectrum Analysis
D007364:Intercalating Agents; D009838:Oligodeoxyribonucleotides; D000677:Amsacrine; D009429:Netropsin; D004247:DNA