Studies on the interaction of anthracycline antibiotics and deoxyribonucleic acid: geometry of intercalation of iremycin and daunomycin

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Abstract
The structure of [the antineoplastic and antimicrobial drug] iremycin [10-(.alpha.-L-rhodosaminyl)-.gamma.-rhodomycinone] hydrochloride was confirmed by 1H- and 13C NMR spectroscopy. The interaction of iremycin and the related [antineoplastic] compound daunomycin with DNA was studied by transient electric dichroism and by sedimentation analysis of supercoiled closed duplex DNA. The apparent length increase of sonicated calf thymus DNA (150 .+-. 20 base pairs) in 2.5 mM sodium cacodylate buffer (pH 7) at 12.degree. C was 0.40 .+-. 0.02 nm/bound iremycin, which is signifcantly higher than the apparent length increase induced by daunomycin (0.31 .+-. 0.02 nm/bound drug). The Cu(II) complex of iremycin with a metal/drug ratio of 0.7 induces a length increase of DNA of 0.44 .+-. 0.02 nm/added drug. The alignment of the iremycin chromophore with respect to the DNA helix axis was determined from the electric dichroism of the complex. The tilt (long axis) and twist (short axis) of the chromophore are both 28 .+-. 4.degree.; for daunomycin the long axis is perpendicular to the helix axis and the short axis is twisted by .apprx. 25.degree.. Intercalation of iremycin between DNA base pairs is supported by unwinding of the supercoiled closed duplex form of pBR322 plasmid DNA from Escherichia coli. In 2.5 mM sodium cacodylate buffer at pH 7 and at 25.degree. C, the unwinding induced by iremycin is 15.0 .+-. 1.5.degree./bound drug. Under identical conditions daunomycin shows on unwinding an angle of 15.4 .+-. 1.5.degree.. The superhelical density of pBR 322 DNA (.hivin..sigma.o) was -0.087 .+-. 0.002 at standard conditions (0.2 M NaCl, 37.degree. C).