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We have performed a quantitative analysis of the interaction with DNA of several unfused aromatic compounds synthesized in our laboratory and substituted with one or two short cationic chains. These and similar literature compounds, for which DNA binding data are available, bind with DNA by partial intercalation of the aromatic system, groove interaction of the linker chain, and groove electrostatic interactions of the terminal cationic group. Several independent quantitative and qualitative approaches show consistently that the strength of the interaction of the aromatic unit of the molecule with DNA binding sites depends on the direction and magnitude of polarity of the aromatic system. The phenomenon is explained in terms of the greatest negative potential in the DNA grooves, a concept extensively elaborated by Pullman and Pullman [cf. Lavery, R. and Pullman, B. [(1985) J. Biomol. Struct. Dyn. 2, 1021-1032] and references therein]. Classical, fused-ring planar intercalators do not follow the polarity-DNA affinity correlation, presumably because the intercalative forces depend more strongly on polarizability than on polarity of the aromatic system.

A set of 21 polyheteroaromatic compounds substituted with flexible cationic groups and of similar molecular size has been analyzed for binding with DNA and for effects of the bleomycin-mediated degradation of the DNA double helix. Increases in apparent rates of the DNA digestion were observed in all cases under the experimental conditions of noncompetitive binding of these compounds and bleomycin to DNA. Surprisingly, the quantitative structure-activity relationship analysis revealed two distinct correlations despite close structural similarities for the set of bleomycin amplifiers. These unusual results are explained in terms of the formation of two stereochemically different ternary complexes of activated bleomycin-DNA-amplifier. The relevance of this finding for the design of new bleomycin amplifiers is discussed.

The bleomycin-mediated digestion of DNA in the presence of ferrous ion, molecular oxygen, and dithiothreitol is characterized by a fast initial reaction, which is followed by a much slower process. The fast degradation is due to the fast activation of the bleomycin-Fe(II) complex and the subsequent fast reaction of the activated complex with DNA. The rate determining step for the slow process is reactivation of the bleomycin-Fe(III) complex. The apparent rate constants for both reactions increase with increasing ionic strength. The latter, unusual results are interpreted in terms of inhibition of bleomycin turnover by binding of cationic species with DNA at low ionic strength.

The degradation of calf thymus DNA by a ferrous complex of bleomycin A2 or Blenoxane (a mixture consisting mainly of BLM-A2 and BLM-B2) is enhanced by polyamines higher than ethylenediamine. The QSAR analysis gave excellent correlation between the experimental amplification results and calculated valence molecular connectivity indices of the third order and path type for the protonated polyamines. A new amplifier of bleomycin activity has been synthesized and its interaction with DNA has been studied. This compound contains a DNA-intercalating moiety and a polyamine portion, two independent amplification systems in the same molecule. The role of the C-terminus of bleomycin as the intramolecular amplifier for the degradation of DNA is discussed.