Hydrogen bonding, overlap geometry, and sequence specificity in anthracycline antitumor antibiotic.DNA complexes in solution.
We have deduced structural aspects of the intercalation complex of the anthracycline antitumor antibiotic daunomycin and its analogs with the synthetic DNA poly(dA-dT) by 1H and 31P NMR in high-salt solution. We demonstrate that the base pairs are intact at the antibiotic binding site and that the anthracycline phenolic hydroxyls form intramolecular hydrogen bonds with the quinone carbonyls and are shielded from solvent in the intercalation complex. The complexation shifts of the exchangeable phenolic and nonexchangeable aromatic protons demonstrate that rings B and C of the anthracycline chromophore overlap with adjacent base pairs, while anthracycline ring D passes right through the intercalation site in the complex. We observe two resolved 31P resonances attributable to the dA-dT and dT-dA phosphodiester linkages in the phosphorus spectra of the neighbor-exclusion daunomycin.poly(dA-dT) complex. This suggests that the anthracycline antitumor antibiotic exhibits a sequence specificity in its intercalation complex with alternating purine-pyrimidine synthetic DNAs in solution. These conclusions on hydrogen bonding and overlap geometry at the intercalation site and sequence specificity for the daunomycin.poly(dA-dT) complex in solution are in agreement with the structure of the daunomycin.dC-dG-dT-dA-dC-dG hexanucleotide duplex crystalline complex at atomic resolution published recently [Quigley, G. J., Wang, A. H.-J., Ughetto, G., van der Marel, G., van Boom, J. H. & Rich, A. (1980) Proc. Natl. Acad. Sci. USA 77, 7204-7208].
D000903:Antibiotics, Antineoplastic; D001483:Base Sequence; D003461:Crystallography; D004247:DNA; D003630:Daunorubicin / Q000031:analogs & derivatives; D006027:Glycosides; D006860:Hydrogen Bonding; D007364:Intercalating Agents; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D009279:Naphthacenes; D009690:Nucleic Acid Conformation; D010710:Phosphates; D011522:Protons; D013329:Structure-Activity Relationship
D000903:Antibiotics, Antineoplastic; D006027:Glycosides; D007364:Intercalating Agents; D009279:Naphthacenes; D010710:Phosphates; D011522:Protons; C031708:11-deoxydaunomycin; D004247:DNA; D003630:Daunorubicin