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. 1991 Jul;35(7):1315–1320. doi: 10.1128/aac.35.7.1315

5'-Alkyl-substituted analogs of 5'-methylthioadenosine as trypanocides.

C J Bacchi 1, J R Sufrin 1, H C Nathan 1, A J Spiess 1, T Hannan 1, J Garofalo 1, K Alecia 1, L Katz 1, N Yarlett 1
PMCID: PMC245164  PMID: 1929287

Abstract

5'-Deoxy-5'-(methylthio)adenosine (MTA) is a by-product of polyamine metabolism and is phosphoryolytically cleaved to adenine and 5-deoxy-5-(methylthio)ribose-1-phosphate (MTR-1-P) by MTA phosphorylase. In eukaryotes, adenine is subsequently salvaged and converted to nucleotides, while MTR-1-P is converted to methionine. We examined 5'-deoxy-5'-substituted analogs of MTA for trypanocidal activity in vitro and in vivo. 5'-Deoxy-5'-(hydroxyethyl)thioadenosine (HETA) and its 5'-bromo,5'-chloro and 5'-fluoro derivatives were cleaved by extracts of the African trypanosome Trypanosoma brucei brucei (Km for MTA, 11.5 microM; Km for HETA, 13.2 microM) in a phosphate-dependent reaction. HETA and the three halo analogs were 50% inhibitory to growth at 0.5 to 5.0 microM in vitro. Inhibition of growth was reversible by exogenous methionine and 2-keto-4-methylthiobutyric acid, an intermediate in methionine synthesis from MTR-1-P. HETA was selected for further study in vivo. When administered by miniosmotic pump (25 to 150 mg/kg/day for 7 days) to mice infected with T. brucei brucei, HETA effected 70 to 90% cure rates. Results of this study indicate that these analogs of MTA are converted to trypanocidal MTR-1-P analogs and that this approach deserves further consideration in the development of novel chemotherapy of trypanosomiasis.

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Selected References

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