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 synth esized to examine whether the stability of the parent APA molecule cou ld be increased without loss of its inhibitory capacity towards ornith ine 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-P L, which was a substrate for cellular acetylating activity like the me thylated APA derivatives. Methylation at the 1 or 3 position of APA di d not increase its stability but markedly changed its inhibitory poten cy towards S-adenosylmethionine decarboxylase and spermidine synthase. Supplementation of cell growth media with 1 mM aminoguanidine markedl y reduced the degradation rate of 1- or 3-Me-APA and APA. All the grow th-retarding effects of the drugs were reversed by addition of 10-20 m u M putrescine or spermidine to the growth media containing a drug con centration of 1 mM, except with APA-PL, which had signs of emergent to xicity 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-difluoro methylornithine (DFMO) in inhibiting DNA synthesis by BHK21/C13 cells.