Slunt K M, Grace J M, Macdonald T L, Pearson R D
Department of Chemistry, University of Virginia, Charlottesville 22901, USA.
Antimicrob Agents Chemother. 1996 Mar;40(3):706-9. doi: 10.1128/AAC.40.3.706.
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.
合成并研究了米托萘醌（4-硝基苯并异喹啉二酮）及其一系列结构类似物，以确定抑制利什曼原虫核及动基体拓扑异构酶II和人类拓扑异构酶II的结构要求。对米托萘醌类似物的构效关系研究表明，存在对利什曼原虫核拓扑异构酶II和人类拓扑异构酶II的选择性靶向，以及在寄生虫中动基体拓扑异构酶II相对于核拓扑异构酶II的差异靶向。米托萘醌类似物似乎具有导致利什曼原虫死亡的多种作用机制，但通过短期试验确定，几种影响动基体而非核拓扑异构酶II的化合物没有细胞毒性。这些研究为利什曼原虫核及动基体拓扑异构酶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。
