Effect of mitonafide analogs on topoisomerase II of Leishmania chagasi.
Effect of mitonafide analogs on topoisomerase II of Leishmania chagasi.
复制标题
米托非类似物对恰加斯利什曼原虫拓扑异构酶 II 的影响。
DOI：
10.1128/aac.40.3.706
复制
发表时间：
1996
期刊：
影响因子：
--
通讯作者：
Pearson,RD
中科院分区：
文献类型：
--
作者：
Slunt,KM;Grace,JM;Macdonald,TL;Pearson,RD
为了确定抑制利什曼核和动粒体拓扑异构酶II和人拓扑异构酶II的结构要求，我们合成并研究了丝裂原虫(4-硝基-苯异喹啉二酮)和一些结构类似物。与丝裂原类似物的构效关系研究表明，在寄生虫中，有选择性靶向利什曼核拓扑异构酶II和人拓扑异构酶II，以及运动蛋白靶向核拓扑异构酶II。丝裂原类似物似乎有多种导致利什曼原虫死亡的作用机制，但通过短期试验确定，几种影响运动质膜但不影响核拓扑异构酶II的化合物没有细胞毒性。这些研究为利什曼核型和动泡型拓扑异构酶II对拓扑异构酶II靶向药物的不同敏感性提供了新的见解。
Mitonafide (4-nitro-benzoisoquinolinedione) and a number of structural analogs were synthesized and studied in order to determine the structural requirements for inhibition of leishmanial nuclear and kinetoplast topoisomerase II and human topoisomerase II. The structure-activity relationship studies with the mitonafide analogs demonstrated that there was selective targeting of leishmanial nuclear topoisomerase II and human topoisomerase II and differential targeting of kinetoplast over nuclear topoisomerase II in the parasite. Mitonafide analogs appeared to have multiple mechanisms of action leading to death of leishmanias, but several compounds that affected kinetoplast but not nuclear topoisomerase II were not cytotoxic as determined by short-term assays. These studies provide new insight into the differential sensitivities of leishmanial nuclear and kinetoplast topoisomerase II to topoisomerase II-targeting drugs.