Actinomycin D, 1H NMR studies on intramolecular interactions and on the planarity of the chromophore

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Abstract
The conformation of actinomycin D in acetone and chloroform solution at different temperatures was studied by 1H NMR spectroscopy. At lower temperature the resonances due to the 2 chromophoric amino protons were observed. These signals exhibit very different resonance positions indicating a severely hindered rotation of the 2-amino group and the presence of a H-bond connecting the 2-amino and the 1-carbonyl groups. In 1H NMR spectra of partially 15N-enriched actinomycin D, the 1JN-H coupling constants at the 2-amino group were determined and a strong sp2 character for the 2-amino nitrogen was deduced. The strong amide character of the 2-amino group is caused by mesomerism involving the 1-carbonyl group. The amino proton signals are sensitive indicators for differences in the spatial relationship of the diverse parts of the actinomycin molecule. At lower temperatures a simultaneous and selective broadening of the .alpha. ring threonine and valine amide proton signals as well as of the 2-amino group resonance was observed, indicating the presence of 1 dynamic process in the molecule which slows down upon temperature reduction. A swinging motion of the N(10) nitrogen through the chromophore plane would explain this observation. The interpretation of these results requires the presence of a non-planar chromophoric system in the actinomycin molecule in acetone and chloroform solution. The possible implications of this non-planarity for the DNA intercalation process and for the biological activity of the drug are discussed.