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: C J Bacchi, K Sanabria, A J Spiess, M Vargas, C J Marasco Jr, L M Jimenez, B Goldberg, J R Sufrin
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 41 Issue 10 Pg. 2108-12 (Oct 1997) ISSN: 0066-4804 [Print] United States
• PMID: 9333033 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Deoxyadenosines
• Thionucleosides
• Trypanocidal Agents
• 5'-methylthioadenosine

Topics

• Animals
• Deoxyadenosines (chemical synthesis, pharmacology, therapeutic use)
• Dose-Response Relationship, Drug
• Mice
• Thionucleosides (chemical synthesis, pharmacology, therapeutic use)
• Trypanocidal Agents (chemical synthesis, pharmacology, therapeutic use)
• Trypanosoma brucei brucei (drug effects)
• Trypanosoma brucei rhodesiense (drug effects)
• Trypanosomiasis, African (drug therapy, parasitology)