The ubiquitous polyamines putrescine, spermidine, and spermine are implicated in cellular growth and/or differentiation.1 Spermidine and spermine have been shown to be transformed back to their respective bioprecursors putrescine and spermidine2 by the action of acetyl CoA: polyamine IV'-acetyltransferase and polyamine oxidase (PAO). This interconversion pathway of polyamines occurs apparently in all mammalian tissues.PAO is a flavin-dependent enzyme3 that catalyzes a reaction closely akin to that performed by monoamine oxidase (MAO, EC 1.4.3.4, flavin dependent). In analogy with the irreversible inhibition of MAO by propargyl-,4 allyl-,5 and 2,3-butadienylamines,6 we have prepared a series of putrescine derivatives substituted on nitrogen Scheme Io e NHBOC

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Complete inhibition of polyamine catabolism is possible by combined administration of two compounds. Aminoguanidine (25 mg/kg body wt., intraperitoneally) inhibits all reactions that are catalysed by copper-containing amine oxidases (CuAO). The products of the CuAO-catalysed reactions cannot be reconverted into polyamines (terminal catabolism) and therefore usually escape observation. N1-Methyl-N2-(buta-2,3-dienyl)butane-1,4-diamine (MDL 72521) is a new inhibitor of polyamine oxidase. It inhibits completely the degradation of N1-acetylspermidine and N1-acetylspermine. The enhanced excretion of N1-acetylspermidine in urine after administration of 20 mg of MDL 72521/day per kg body wt. is a measure of the rate of spermidine degradation in vivo to putrescine, and thus of the quantitative significance of the interconversion pathway. From the enhancement of total polyamine excretion by aminoguanidine-treated rats, one can calculate that only about 40% of the polyamines that are destined for elimination are usually observed in the urine, the other 60% being catabolized along the CuAO-catalysed pathways. The normally observed urinary polyamine pattern gives, therefore, an unsatisfactory picture of the actual polyamine elimination. Although aminoguanidine alone is sufficient to block terminal polyamine catabolism, rats that were treated with a combination of aminoguanidine and MDL 72521 excrete more polyamines than those that received aminoguanidine alone. The reason is that a certain proportion of putrescine, which is formed by degradation of spermidine, is normally reutilized for polyamine biosynthesis. In MDL 72521-treated animals this proportion appears in the urine in the form of N1-acetylspermidine. Thus it is possible to determine polyamine interconversion and re-utilization in vivo and to establish a polyamine balance in intact rats by using specific inhibitors of the CuAO and of polyamine oxidase.

The alpha-tocopherol analogue 3,4-dihydro-6-hydroxy-N,N,N,2,5,7,8- heptamethyl-2H-1-benzopyran-2-ethanaminium 4-methylbenzenesulfonate (1a, MDL 73404) and its O-acetate 1b (MDL 74270) were synthesized. Compound 1a was found to be hydrophilic (log P = -0.60) and to prevent lipid autoxidation in rat brain homogenate with an IC50 of 1.7 +/- 0.9 microM. Tissue distribution studies with [14C]-1b in rats (1 mg/kg iv) showed that radioactivity accumulates in the heart (ratio 20:1 vs blood after 1 h). Infusion of 1 mg/kg per h of 1b bromide reduced infarct size by 54% in rats subjected to coronary artery occlusion for 60 min followed by reperfusion for 30 min, compared to saline-infused controls. By comparison, the tertiary amine analogue 5 was found not to accumulate in heart tissue, to be an equally effective free-radical scavenger in vitro, but to require a higher dose to reduce infarct size in rats. This shows that the cardioselectivity of compound 1 contributes to its potency in salvaging myocardial tissue in rats after ischemia and reperfusion.

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