Studies on the metabolic effects of methylthioformycin.

Abstract

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.

• Authors: M Cartenì-Farina, G Cacciapuoti, M Porcelli, F Della Ragione, M Lancieri, G Geraci, V Zappia
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 805 Issue 2 Pg. 158-64 (Oct 12 1984) ISSN: 0006-3002 [Print] Netherlands
• PMID: 6435689 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Deoxyadenosines
• Formycins
• Thionucleosides
• 5'-methylthioadenosine
• 5'-methylthioformycin
• Purine-Nucleoside Phosphorylase
• 5'-methylthioadenosine phosphorylase
• Spermidine Synthase
• Spermine Synthase
• Hydrolases
• Adenosylhomocysteinase
• Adenosine

Topics

• Adenosine (analogs & derivatives, pharmacology)
• Adenosylhomocysteinase
• Animals
• Antibiotics, Antineoplastic (pharmacology)
• Brain (enzymology)
• Cell Division (drug effects)
• Cell Membrane Permeability
• Deoxyadenosines
• Erythrocytes (metabolism)
• Formycins (metabolism, pharmacology)
• Friend murine leukemia virus
• Humans
• Hydrolases (antagonists & inhibitors)
• Leukemia, Erythroblastic, Acute (metabolism, pathology)
• Liver (enzymology)
• Purine-Nucleoside Phosphorylase (antagonists & inhibitors)
• Rats
• Spermidine Synthase (antagonists & inhibitors)
• Spermine Synthase (antagonists & inhibitors)
• Thionucleosides (pharmacology)