Abstract.

In this work we use single molecule force spectroscopy performed with optical tweezers in order to characterize the complexes formed between the anticancer drug Pixantrone (PIX) and the DNA molecule, at two very different ionic strengths. Firstly, the changes of the mechanical properties of the DNA-PIX complexes were studied as a function of the drug concentration in the sample. Then, a quenched-disorder statistical model of ligand binding was used in order to determine the physicochemical (binding) parameters of the DNA-PIX interaction. In particular, we have found that the PIX molecular mechanism of action involves intercalation into the double helix, followed by a significant compaction of the DNA molecule due to partial neutralization of the phosphate backbone. Finally, this scenario of interaction was quantitatively compared to that found for the related drug Mitoxantrone (MTX), which binds to DNA with a considerably higher equilibrium binding constant and promotes a much stronger DNA compaction. The comparison performed between the two drugs can bring clues to the development of new (and more efficient) related compounds.

Graphical abstract

中文翻译：

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吡咯烷酮抗癌药作为DNA配体：描述了单分子水平的作用机理。

摘要。

在这项工作中，我们使用通过光镊进行的单分子力光谱法，以表征抗癌药Pixantrone（PIX）与DNA分子之间形成的两种非常不同的离子强度的复合物。首先，研究了DNA-PIX复合物的机械性能随样品中药物浓度的变化。然后，使用配体结合的猝灭统计模型来确定DNA-PIX相互作用的物理化学（结合）参数。尤其是，我们发现PIX分子的作用机理涉及插入双螺旋结构，然后由于磷酸盐骨架的部分中和作用而使DNA分子显着压缩。最后，将这种相互作用的情况与相关药物米托蒽醌（MTX）进行了定量比较，后者以相当高的平衡结合常数与DNA结合并促进了更强的DNA紧密性。两种药物之间进行的比较可以为开发新的（和更有效的）相关化合物提供线索。

图形概要