5'-Alkyl-substituted analogs of 5'-methylthioadenosine as trypanocides.
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.
Haskins Laboratory, Pace University, New York, New York 10038.
C J
CJ
Bacchi
J R
JR
Sufrin
H C
HC
Nathan
A J
AJ
Spiess
T
T
Hannan
J
J
Garofalo
K
K
Alecia
L
L
Katz
N
N
Yarlett
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D003839:Deoxyadenosines; D008715:Methionine / Q000096:biosynthesis; D051379:Mice; D011683:Purine-Nucleoside Phosphorylase / Q000378:metabolism; D051381:Rats; D013872:Thionucleosides / Q000494:pharmacology*; D014344:Trypanocidal Agents; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development
D003839:Deoxyadenosines; D013872:Thionucleosides; D014344:Trypanocidal Agents; C008500:5'-methylthioadenosine; D008715:Methionine; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase; D000241:Adenosine