EFFECT OF MITONAFIDE ANALOGS ON TOPOISOMERASE-II OF LEISHMANIA-CHAGASI

Mitonafide (4-nitro-benzoisoquinolinedione) and a number of structural analogs were synthesized and studied in order to determine the struct ural requirements for inhibition of leishmanial nuclear and kinetoplas t topoisomerase II and human topoisomerase II. The structure-activity relationship studies with the mitonafide analogs demonstrated that the re 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 topo isomerase II were not cytotoxic as determined by short-term assays. Th ese studies provide new insight into the differential sensitivities of leishmanial nuclear and kinetoplast topoisomerase II to topoisomerase II-targeting drugs.