Scaria P V, Craig J C, Shafer R H
Department of Pharmaceutical Chemistry, University of California, San Francisco 94143.
Biopolymers. 1993 Jun;33(6):887-95. doi: 10.1002/bip.360330604.
Interaction of the antimalarial drugs quinacrine and chloroquine with DNA has been studied extensively in order to understand the origin of their biological activity. These studies have shown that they bind to DNA through an intercalative mode and show little sequence specificity. All previous experiments were carried out using the racemic form of these drugs. We have investigated the binding of the enantiomeric forms of quinacrine and chloroquine to synthetic polynucleotides poly(dA-dT).poly(dA-dT) and poly(dG-dC).poly (dG-dC), and found interesting differences in their binding parameters. Quinacrine enantiomers have a much higher binding affinity for the two polynucleotides compared to those of chloroquine. The negative enantiomers were found to have higher binding affinity than the positive ones. The binding constant for the binding of quinacrine(-) to poly(dG-dC).poly(dG-dC) was found to be about 3 times that of quinacrine(+). The differences in these binding affinities were further confirmed by equilibrium dialysis of the complexes of the polynucleotides with the racemic form of the drugs, which resulted in the enrichment of the dialysate with the positive enantiomer. CD spectra of the enantiomers and their polynucleotide complexes are reported. Changes in the fluorescence properties of quinacrine in the presence of the two polynucleotides are also described. Biological implications of these findings are discussed.
为了理解抗疟药物奎纳克林和氯喹的生物活性来源，人们对它们与DNA的相互作用进行了广泛研究。这些研究表明，它们通过嵌入模式与DNA结合，且序列特异性较低。此前所有实验均使用这些药物的外消旋形式进行。我们研究了奎纳克林和氯喹对映体与合成多核苷酸聚（dA-dT）·聚（dA-dT）和聚（dG-dC）·聚（dG-dC）的结合情况，发现它们的结合参数存在有趣的差异。与氯喹对映体相比，奎纳克林对映体对这两种多核苷酸具有更高的结合亲和力。发现负对映体的结合亲和力高于正对映体。奎纳克林（-）与聚（dG-dC）·聚（dG-dC）结合的结合常数约为奎纳克林（+）的3倍。通过对多核苷酸与药物外消旋形式的复合物进行平衡透析，进一步证实了这些结合亲和力的差异，透析结果是透析液中富集了正对映体。报道了对映体及其多核苷酸复合物的圆二色谱。还描述了在两种多核苷酸存在下奎纳克林荧光性质的变化。讨论了这些发现的生物学意义。
