title: Derivatives of Dictyostelium discoideum differentiation-inducing factor-3 suppress the activities of Trypanosoma cruzi in vitro and in vivo.
abstract: Chagas disease (human American trypanosomiasis), which is caused by the protozoan parasite Trypanosoma cruzi, is responsible for numerous deaths each year; however, established treatments for the disease are limited. Differentiation-inducing factor-1 (DIF-1) and DIF-3 are chlorinated alkylphenones originally found in the cellular slime mold Dictyostelium discoideum that have been shown to possess pharmacological activities. Here, we investigated the effects of DIF-3 derivatives on the infection rate and growth of T. cruzi by using an in vitro assay system utilizing host human fibrosarcoma HT1080 cells. Certain DIF-3 derivatives, such as butoxy-DIF-3 (Bu-DIF-3), at micro-molar levels strongly suppressed both the infection rate and growth of T. cruzi in HT1080 cells and exhibited little toxicity for HT1080 cells. For example, the IC50 of DIF-3 and Bu-DIF-3 versus the growth of T. cruzi in HT1080 cells were 3.95 and 0.72μM, respectively, and the LD50 of the two compounds versus HT1080 cells were both greater than 100μM. We also examined the effects of DIF-3 and Bu-DIF-3 on T. cruzi activity in C57BL/6 mice. Intraperitoneally administered Bu-DIF-3 (50mg/kg) significantly suppressed the number of trypomastigotes in blood with no apparent adverse effects. These results strongly suggest that DIF-3 derivatives could be new lead compounds in the development of anti-trypanosomiasis drugs.
authors.affiliation: Department of Molecular and Cellular Parasitology, Graduate School of Health Sciences, Gunma University, Maebashi 371-8514, Japan. jshimada@health.gunma-u.ac.jp
authors.forename: Junko
authors.initials: J
authors.lastname: Nakajima-Shimada
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Hatabu
authors.forename: Yukari
authors.initials: Y
authors.lastname: Hosoi
authors.forename: Yoko
authors.initials: Y
authors.lastname: Onizuka
authors.forename: Haruhisa
authors.initials: H
authors.lastname: Kikuchi
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Oshima
authors.forename: Yuzuru
authors.initials: Y
authors.lastname: Kubohara
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D004023:Dictyostelium / Q000166:cytology*; D006588:Hexanones / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D060888:Real-Time Polymerase Chain Reaction; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000502:physiology
chemical_list: D017931:DNA Primers; D006588:Hexanones; C055364:1-(3-chloro-2,6-dihydroxy-4-methoxyphenyl)-1-hexanone