Synthesis of Isoornithines and Methylputrescines. An Evaluation of Their Inhibitory Effects on Ornithine Decarboxylase

2-(Aminomethyl)-4-aminobutyric acid (isoornithine), 3-methylisoornithine, and 2,3-dimethylisoornithine were not decarboxylated by liver ornithine decarboxylase (ODC, EC 4.1.1.17) of thioacetamide-treated rats but were good competitive inhibitors of the enzyme (Ki ranged from 0.72 to 1.79 mM). When a...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1995-10, Vol.38 (21), p.4337-4341
Main Authors: Aizencang, Gerardo, Frydman, Rosalia B, Giorgieri, Sergio, Sambrotta, Luis, Guerra, Liliana, Frydman, Benjamin
Format: Article
Language:English
Subjects:
Analytical, structural and metabolic biochemistry
Animals
Binding, Competitive
Biological and medical sciences
Carcinoma, Hepatocellular
Enzyme Inhibitors - pharmacology
Enzymes and enzyme inhibitors
Fundamental and applied biological sciences. Psychology
Liver - drug effects
Liver - enzymology
Liver Neoplasms
Lyases
Ornithine - analogs & derivatives
Ornithine - chemistry
Ornithine - metabolism
Ornithine Decarboxylase Inhibitors
Putrescine - analogs & derivatives
Putrescine - chemistry
Putrescine - metabolism
Rats
Structure-Activity Relationship
Thioacetamide - pharmacology
Tumor Cells, Cultured
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Summary:2-(Aminomethyl)-4-aminobutyric acid (isoornithine), 3-methylisoornithine, and 2,3-dimethylisoornithine were not decarboxylated by liver ornithine decarboxylase (ODC, EC 4.1.1.17) of thioacetamide-treated rats but were good competitive inhibitors of the enzyme (Ki ranged from 0.72 to 1.79 mM). When assayed in vivo in the treated rats, the above mentioned isoornithines were also found to inhibit liver ODC when administered 1 h before sacrifice. When the methylputrescines formally derived from the decarboxylation of several isoornithines were assayed on rat liver ODC, it was found that only 2,3-dimethylputrescine decreased the enzymatic activity. When assayed in vivo, it was found to decrease ODC activity by 60%, when the latter was measured 1 h after administration. The effect was reverted 4 h after administration of the drug. Isoornithines were not taken up by H-35 hepatoma cells; hence they did not affect their ODC activity. 2,3-Dimethylputrescine however, was transported into the cells and significantly decreased its ODC activity.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00021a024