Werbovetz K A, Spoors P G, Pearson R D, Macdonald T L
Department of Chemistry, University of Virginia, Charlottesville 22901.
Mol Biochem Parasitol. 1994 May;65(1):1-10. doi: 10.1016/0166-6851(94)90110-4.
Anilinoacridines have recently been found to possess antiparasitic activity toward Leishmania, Trypanosoma, and Plasmodium species. These compounds have been examined for their ability to generate cleavable complex, the protein-associated DNA lesion characteristic of topoisomerase II involvement, in intact L. chagasi promastigotes. At cytotoxic concentrations, anilinoacridine compounds give cleavable complex in a whole cell assay which suggests that the drugs affect a nuclear topoisomerase II in the parasite. Linearization of kinetoplast DNA minicircles also occurs in parasites treated with anilinoacridines at similar concentrations. Exonuclease digestions reveal that the linearized minicircles are blocked at the 5' end but not at the 3' end, further implicating a kinetoplast topoisomerase II in the cleavage process. Interestingly, cytotoxic alkylaminoacridines did not stimulate the production of cleaved DNA in the same experiments. DNA binding experiments showed no apparent correlation between the affinity of the compounds for DNA and antileishmanial activity. Although multiple cytotoxic mechanisms are likely at work, these experiments suggest that topoisomerase II enzyme(s) are affected by antileishmanial anilinoacridines.
近来发现苯胺吖啶对利什曼原虫、锥虫和疟原虫具有抗寄生虫活性。已检测了这些化合物在完整的恰加斯氏利什曼原虫前鞭毛体中产生可切割复合物的能力，这种复合物是与拓扑异构酶II参与相关的蛋白质-DNA损伤的特征。在细胞毒性浓度下，苯胺吖啶化合物在全细胞试验中产生可切割复合物，这表明这些药物影响寄生虫中的一种核拓扑异构酶II。在以相似浓度用苯胺吖啶处理的寄生虫中，动质体DNA小环也会发生线性化。核酸外切酶消化显示，线性化的小环在5'端被阻断，但在3'端未被阻断，这进一步表明动质体拓扑异构酶II参与了切割过程。有趣的是，在相同实验中，细胞毒性烷基氨基吖啶并未刺激切割DNA的产生。DNA结合实验表明，这些化合物对DNA的亲和力与抗利什曼活性之间没有明显的相关性。尽管可能存在多种细胞毒性机制在起作用，但这些实验表明抗利什曼苯胺吖啶会影响拓扑异构酶II酶。
