title: Derivatives of 1-aminooxy-3-aminopropane as polyamine antimetabolites: stability and effects on BHK21/C13 cells.
abstract: 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.
authors.affiliation: Department of Biochemistry and Biotechnology, University of Kuopio, Finland.
authors.forename: T A
authors.initials: TA
authors.lastname: Keinänen
authors.forename: T
authors.initials: T
authors.lastname: Hyvönen
authors.forename: M C
authors.initials: MC
authors.lastname: Pankaskie
authors.forename: J J
authors.initials: JJ
authors.lastname: Vepsäläinen
authors.forename: T O
authors.initials: TO
authors.lastname: Eloranta
mesh_terms: D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors; D000818:Animals; D002082:Butylamines / Q000138:chemical synthesis / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D006224:Cricetinae; D004261:DNA Replication / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology; D065108:Ornithine Decarboxylase Inhibitors; D011437:Propylamines / Q000494:pharmacology*; D011436:Spermidine Synthase / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
chemical_list: C092696:1-aminooxy-1-methyl-3-aminopropane; C092695:1-aminooxy-3-methyl-3-aminopropane; D002082:Butylamines; D006146:Guanidines; D065108:Ornithine Decarboxylase Inhibitors; D011437:Propylamines; C046252:1-aminooxy-3-aminopropane; D011436:Spermidine Synthase; D012437:Adenosylmethionine Decarboxylase; C004479:pimagedine