Derivatives of 1-aminooxy-3-aminopropane as polyamine antimetabolites: stability and effects on BHK21/C13 cells

1- or 3-methylated derivatives and oximes of 1-aminooxy-3-aminopropane (APA) with pyridoxal (PL) and pyridoxal 5'-phosphate (PLP) were synthesized to examine whether the stability of the parent APA molecule could be increased without loss of its inhibitory capacity towards ornithine decarboxyla...

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Bibliographic Details
Published in:Journal of biochemistry (Tokyo) 1994-11, Vol.116 (5), p.1056
Main Authors: Keinänen, T A, Hyvönen, T, Pankaskie, M C, Vepsäläinen, J J, Eloranta, T O
Format: Article
Language:English
Subjects:
Adenosylmethionine Decarboxylase - antagonists & inhibitors
Animals
Butylamines - chemical synthesis
Butylamines - pharmacology
Cell Division - drug effects
Cell Line
Cricetinae
DNA Replication - drug effects
Guanidines - pharmacology
Ornithine Decarboxylase Inhibitors
Propylamines - pharmacology
Spermidine Synthase - antagonists & inhibitors
Structure-Activity Relationship
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Summary:1- or 3-methylated derivatives and oximes of 1-aminooxy-3-aminopropane (APA) with pyridoxal (PL) and pyridoxal 5'-phosphate (PLP) were synthesized to examine whether the stability of the parent APA molecule could be increased without loss of its inhibitory capacity towards ornithine decarboxylase. Preformed APA-PLP was more stable than APA and was not a substrate of cellular acetylating activity. The only detectable degradation mechanism of APA-PLP was a slow dephosphorylation to APA-PL, which was a substrate for cellular acetylating activity like the methylated APA derivatives. Methylation at the 1 or 3 position of APA did not increase its stability but markedly changed its inhibitory potency towards S-adenosylmethionine decarboxylase and spermidine synthase. Supplementation of cell growth media with 1 mM aminoguanidine markedly reduced the degradation rate of 1- or 3-Me-APA and APA. All the growth-retarding effects of the drugs were reversed by addition of 10-20 microM putrescine or spermidine to the growth media containing a drug concentration of 1 mM, except with APA-PL, which had signs of emergent toxicity at concentrations above 0.5 mM. APA-PL and APA-PLP were as good as APA and two orders of magnitude more effective than alpha-difluoromethylornithine (DFMO) in inhibiting DNA synthesis by BHK21/C13 cells.
ISSN:0021-924X
DOI:10.1093/oxfordjournals.jbchem.a124627