title: Selective anti-Toxoplasma gondii activities of azasterols.
abstract: We report potent and selective inhibitory effects of 22,26-azasterol and 24,25-(R,S)-epiminolanosterol, known inhibitors of Delta24(25)-sterol methyltranferase (SMT) in fungi and protozoa, on the proliferation of Toxoplasma gondii in LLCMK2 cells. These compounds produced a dose-dependent reduction in parasite proliferation. 22,26-azasterol had an IC50 of 5.3 microM after 24 h and 4.5 microM after 48 h, while for 24,25-(R,S)-epiminolanosterol the IC50 values were 1 microM after 24 h and 0.12 microM after 48 h. The rapid reduction of parasite load suggested these compounds have selective cytotoxic effects against T. gondii. However, we were unable to detect 24-alkyl sterols in purified T. gondii tachyzoites using highly sensitive gas-liquid chromatography/mass spectrometry methods, a fact which indicated that the anti-proliferative effects of these azasterols were not mediated by inhibition of SMT. Transmission electron microscopy showed that the mitochondrion was the major target of drugs. Ultrastructural effects on plasma membrane, apicoplast and the formation of autophagosomal structures were also observed.
authors.affiliation: Laboratório de Ultraestrutura Celular Hertha Meyer, Instituto de Biofísica Carlos Chagas Filho, Bloco G, CCS, Universidade Federal do Rio de Janeiro, 21949-9000 Rio de Janeiro, RJ, Brazil.
authors.forename: Lucas
authors.initials: L
authors.lastname: Dantas-Leite
authors.forename: Julio A
authors.initials: JA
authors.lastname: Urbina
authors.forename: Wanderley
authors.initials: W
authors.lastname: de Souza
authors.forename: Rossiane C
authors.initials: RC
authors.lastname: Vommaro
mesh_terms: D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000648:ultrastructure; D004083:Cholestanol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D003049:Coccidiostats / Q000494:pharmacology*; D008401:Gas Chromatography-Mass Spectrometry; D007810:Lanosterol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008253:Macaca mulatta; D008780:Methyltransferases / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure; D021261:Parasitic Sensitivity Tests; D010588:Phagosomes / Q000187:drug effects / Q000648:ultrastructure; D013261:Sterols / Q000032:analysis; D014122:Toxoplasma / Q000737:chemistry / Q000187:drug effects* / Q000254:growth & development / Q000648:ultrastructure
chemical_list: C103731:22,26-azasterol; D003049:Coccidiostats; D013261:Sterols; C059162:24,25-iminolanosterol; D007810:Lanosterol; D004083:Cholestanol; D008780:Methyltransferases; C022670:delta 24-sterol methyltransferase