Molecular basis for bleomycin amplification: conformational and stereoelectronic effects in unfused amplifiers

Sixteen unfused heterobiaromatic and biphenyl compounds substituted with an amino side chain (protonated in water) have been tested for (i) binding with DNA and (ii) their effect on the digestion of the DNA double helix by a bleomycin-iron complex. Only the DNA intercalating molecules amplify the digestion of DNA. One 2,2'-bipyridine derivative tested is an inhibitor of the bleomycin reaction because it removes ferrous ion from the bleomycin complex. Polarity of the intercalating unfused biaromatic system is of primary importance for effective binding of the molecule with native DNA and, at the same time, for its amplification activity. The molecules that have the biaromatic system polarized extensively in the direction of the side cationic chain, so that the intercalating sites constitutes a positive part of the dipole, show strong binding with DNA and good amplification activity. For strong intercalative forces that determine the amplification activity, it is important that both the heteroaromatic subsystems of the molecule have positive ends of their dipoles positioned away from the side chain. This work provides general guidelines for synthesis of new highly effective bleomycin amplifiers.