Two-dimensional 1H and 31P NMR spectra of a decamer oligodeoxyribonucleotide duplex and a quinoxaline ((MeCys3, MeCys7)(TANDEM) drug duplex complex.
Assignment of the 1H and 31P NMR spectra of a decamer oligodeoxyribonucleotide duplex, d(CCCGATCGGG), and its quinoxaline ((MeCys3, MeCys7]TANDEM) drug duplex complex has been made by two-dimensional 1H-1H and heteronuclear 31P-1H correlated spectroscopy. The 31P chemical shifts of this 10 base pair oligonucleotide follow the general observation that the more internal the phosphate is located within the oligonucleotide sequence, the more upfield the 31P resonance occurs. While the 31P chemical shifts show sequence-specific variations, they also do not generally follow the Calladine "rules" previously demonstrated. 31P NMR also provides a convenient monitor of the phosphate ester backbone conformational changes upon binding of the drug to the duplex. Although the quinoxaline drug, [MeCys3, MeCys7]TANDEM, is generally expected to bind to duplex DNA by bis-intercalation, only small 31P chemical shift changes are observed upon binding the drug to duplex d(CCCGATCGGG). Additionally, only small perturbations in the 1H NMR and UV spectra are observed upon binding the drug to the decamer, although association of the drug stabilizes the duplex form relative to the other states. These results are consistent with a non-intercalative mode of association of the drug. Modeling and molecular mechanics energy minimization demonstrate that a novel structure in which the two quinoxaline rings of the drug binds in the minor groove of the duplex is possible.
Powers
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Department of Chemistry, Purdue University, West Lafayette, Indiana 47907.
Olsen
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Gorenstein
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D000818:Animals; D001483:Base Sequence; D004247:DNA; D007364:Intercalating Agents / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D051379:Mice; D008958:Models, Molecular; D009838:Oligodeoxyribonucleotides; D011810:Quinoxalines / Q000378:metabolism / Q000493:pharmacokinetics; D013696:Temperature; D013816:Thermodynamics; D014466:Ultraviolet Rays
D007364:Intercalating Agents; D009838:Oligodeoxyribonucleotides; D011810:Quinoxalines; C017738:TANDEM (quinoxaline); D004247:DNA