title: In vivo efficacies of 5'-methylthioadenosine analogs as trypanocides.
abstract: 5'-Deoxy-5'-(methylthio)adenosine (MTA), a key by-product of polyamine biosynthesis, is cleaved by MTA phosphorylase and is salvaged as adenine and, through conversion of the ribose moiety, methionine. An analog of MTA, 5'-deoxy-5'-(hydroxyethylthio)adenosine (HETA), is a substrate for trypanosome MTA phosphorylase and is active in vitro and in vivo against Trypanosoma brucei brucei, an agent of bovine trypanosomiasis. In this study, HETA and three O-acylated HETA derivatives were examined for their activities against model infections of T. b. brucei and Trypanosoma brucei rhodesiense, the agent of East African sleeping sickness. HETA was curative (>60%) for infections caused by 5 of 11 clinical isolates of T. b. rhodesiense when it was given to mice at 200 mg/kg of body weight for 7 days as a continuous infusion in osmotic pumps. HETA at 150 to 200 mg/kg also extended the life spans of the mice infected with four additional isolates two- to fivefold. Di- and tri-O-acetylated derivatives of HETA also proved curative for the infections, while a tri-O-propionyl derivative, although also curative, was not as effective. This study indicates that substrate analogs of MTA should be given important consideration for development as novel chemotherapies against African trypanosomiasis.
authors.affiliation: Department of Biology, Pace University, New York, New York 10038, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Bacchi
authors.forename: K
authors.initials: K
authors.lastname: Sanabria
authors.forename: A J
authors.initials: AJ
authors.lastname: Spiess
authors.forename: M
authors.initials: M
authors.lastname: Vargas
authors.forename: C J
authors.initials: CJ
authors.lastname: Marasco
authors.forename: L M
authors.initials: LM
authors.lastname: Jimenez
authors.forename: B
authors.initials: B
authors.lastname: Goldberg
authors.forename: J R
authors.initials: JR
authors.lastname: Sufrin
mesh_terms: D000818:Animals; D003839:Deoxyadenosines / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D051379:Mice; D013872:Thionucleosides / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D014346:Trypanosoma brucei brucei / Q000187:drug effects*; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects*; D014353:Trypanosomiasis, African / Q000188:drug therapy* / Q000469:parasitology*
chemical_list: D003839:Deoxyadenosines; D013872:Thionucleosides; D014344:Trypanocidal Agents; C008500:5'-methylthioadenosine