Strekowski L, Mokrosz J L, Tanious F A, Watson R A, Harden D, Mokrosz M, Edwards W D, Wilson W D
Department of Chemistry, Georgia State University, Atlanta 30303-3083.
J Med Chem. 1988 Jun;31(6):1231-40. doi: 10.1021/jm00401a027.
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.
十六种带有氨基侧链（在水中质子化）的未稠合杂双芳香族和联苯化合物已被测试用于：（i）与DNA结合，以及（ii）它们对博来霉素 - 铁复合物消化DNA双螺旋的影响。只有DNA嵌入分子会增强DNA的消化。所测试的一种2,2'-联吡啶衍生物是博来霉素反应的抑制剂，因为它会从博来霉素复合物中去除亚铁离子。未稠合的双芳香族嵌入体系的极性对于分子与天然DNA的有效结合以及同时对于其增强活性至关重要。那些双芳香族体系在侧阳离子链方向上有广泛极化，使得嵌入位点构成偶极子正端的分子，显示出与DNA的强结合以及良好的增强活性。对于决定增强活性的强嵌入力而言，重要的是分子的两个杂芳香族子体系的偶极正端都远离侧链。这项工作为新型高效博来霉素增强剂的合成提供了总体指导方针。
