BACKGROUND & AIMS:
The first order rate constants for the dissociation of daunorubicin, doxorubicin, and 1-; 1,4-; 1,5-; and 1,8-; N,N-diethylaminoethylamino-substituted anthraquinones from calf thymus DNA were determined using stopped-flow spectrophotometry. Sodium dodecyl sulphate was used to disrupt the equilibrium. In all cases there was an increase in the rate constant with temperature. The dissociation rate constants at 20 degrees, 25 degrees and 37 degrees, were in the order 1-; much greater than 1,8-; greater than 1,4-; greater than daunorubicin and doxorubicin greater than 1,5-disubstituted anthraquinone. The 1,5-disubstituted anthraquinone (VII) thus shows the slowest rate of dissociation from DNA; the DNA complex dissociating more slowly than the DNA complexes of the anthracyclines, daunorubicin and doxorubicin. The result is consistent with the data from computer graphics modelling studies [39] which show that DNA-breathing (transient base pair unstacking) has to occur to allow the docking of the 1,5-disubstituted anthraquinone (VII) into the receptor site. Hence once the 1,5-disubstituted anthraquinone molecule has intercalated into DNA, DNA-breathing is required before dissociation can take place. This is not necessary with the other compounds (though the 1,4-disubstituted anthraquinone (V) can bind in this manner as well). So the very slow dissociation of the DNA/1,5-disubstituted anthraquinone complex relative to that of the DNA complexes of the other compounds examined here, supports the proposed mode of binding [39].
背景与目标:
柔红霉素,阿霉素和1-解离的一级速率常数; 1,4-; 1,5-;和1,8-;使用停止流光度法测定小牛胸腺DNA中N,N-二乙基氨基乙基氨基取代的蒽醌。用十二烷基硫酸钠破坏平衡。在所有情况下,速率常数均随温度增加。在20度,25度和37度下的解离速率常数为1-的数量级;远远大于1,8-;大于1,4-;大于柔红霉素和阿霉素大于1,5-二取代的蒽醌。因此,1,5-二取代的蒽醌(VII)显示出从DNA解离的最慢速率。与蒽环霉素,柔红霉素和阿霉素的DNA复合物相比,DNA复合物解离的速度更慢。结果与计算机图形学研究的数据一致[39],该研究表明必须进行DNA呼吸(瞬态碱基对解叠)才能将1,5-二取代的蒽醌(VII)对接到受体位点。因此,一旦1,5-二取代的蒽醌分子插入DNA中,就需要进行DNA呼吸,然后才能发生解离。对于其他化合物,这不是必需的(尽管1,4-二取代的蒽醌(V)也可以这种方式结合)。因此,DNA / 1,5-二取代蒽醌复合物的解离速度相对于此处检测的其他化合物的DNA络合物而言非常缓慢,支持拟议的结合方式[39]。