Studies on the metabolic effects of methylthioformycin.
5'-Methylthioformycin, a structural analog of 5'-methylthioadenosine in which the N-C glycosidic bond is substituted by a C-C bond, has been synthesized by a newly developed procedure. Membrane permeability of the molecule has been compared to that of methylthioadenosine in intact human erythrocytes and Friend erythroleukemia cells. The formycinyl compound is taken up with a rate significantly lower than that of 5'-methylthioadenosine and is not metabolized by the cells. 5'-Methylthioformycin inhibits Friend erythroleukemia cells' growth: the effect is dose-dependent, fully reversible and not caused by cytotoxicity. Several enzymes related to methylthioadenosine metabolism are inhibited by methylthioformycin. Rat liver methylthioadenosine phosphorylase is competitively inhibited with a Ki value of 2 microM. Among the propylamine transferases tested only rat brain spermine synthase is significantly inhibited, while rat brain spermidine synthase is less sensitive. Rat liver S-adenosylhomocysteine hydrolase is irreversibly inactivated with 50% inhibition at 400 microM methylthioformycin. 5'-Methylthioformycin does not exert any significant effect on protein carboxyl-O-methyltransferase. Inferences about the mechanism of the antiproliferative effect of the drug have been drawn from the above results.
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D043383:Adenosylhomocysteinase; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001921:Brain / Q000201:enzymology; D002455:Cell Division / Q000187:drug effects; D002463:Cell Membrane Permeability; D003839:Deoxyadenosines; D004912:Erythrocytes / Q000378:metabolism; D005573:Formycins / Q000378:metabolism / Q000494:pharmacology*; D005622:Friend murine leukemia virus; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors; D004915:Leukemia, Erythroblastic, Acute / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000201:enzymology; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors; D051381:Rats; D011436:Spermidine Synthase / Q000037:antagonists & inhibitors; D013097:Spermine Synthase / Q000037:antagonists & inhibitors; D013872:Thionucleosides / Q000494:pharmacology*
D000903:Antibiotics, Antineoplastic; D003839:Deoxyadenosines; D005573:Formycins; D013872:Thionucleosides; C008500:5'-methylthioadenosine; C043126:5'-methylthioformycin; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase; D011436:Spermidine Synthase; D013097:Spermine Synthase; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000241:Adenosine