Studies on interaction of anthracycline antibiotics and deoxyribonucleic acid: geometry of intercalation of iremycin and daunomycin.
The structure of iremycin [10-(alpha-L-rhodosaminyl)-gamma-rhodomycinone] hydrochloride has been confirmed by 1H and 13C nuclear magnetic resonance (NMR) spectroscopy. We studied the interaction of iremycin and the related compound daunomycin with DNA 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 degrees C was determined to be 0.40 +/- 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 degrees, whereas for daunomycin the long axis is perpendicular to the helix axis and the short axis is twisted by about 25 degrees. Intercalation of iremycin between DNA base pairs is supported by unwinding of the supercoiled closed duplex form of pBR 322 plasmid DNA from Escherichia coli. In 2.5 mM sodium cacodylate buffer at pH 7 and at 25 degrees C, the unwinding induced by iremycin is 15.0 +/- 1.5 degrees/bound drug. Under identical conditions daunomycin shows on unwinding angle of 15.4 +/- 1.5 degrees. The superhelical density of pBR 322 DNA (sigma 0) was determined to be -0.087 +/- 0.002 at standard conditions (0.2 M NaCl, 37 degrees C).
D018943:Anthracyclines; D000900:Anti-Bacterial Agents / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D004247:DNA / Q000378:metabolism*; D004269:DNA, Bacterial / Q000378:metabolism; D004278:DNA, Superhelical / Q000378:metabolism; D003630:Daunorubicin / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D009279:Naphthacenes / Q000378:metabolism; D009690:Nucleic Acid Conformation; D013057:Spectrum Analysis
D018943:Anthracyclines; D000900:Anti-Bacterial Agents; D004269:DNA, Bacterial; D004278:DNA, Superhelical; D009279:Naphthacenes; C028700:iremycin; D004247:DNA; D003630:Daunorubicin