Abstract
Homeostasis of the biogenic polyamines spermine (Spm) and spermidine (Spd), present in μM-mM concentrations in all eukaryotic cells, is precisely regulated by coordinated activities of the enzymes of polyamine synthesis, degradation, and transport, in order to sustain normal cell growth and viability. Spermine oxidase (SMOX) is the key and most recently discovered enzyme of polyamine metabolism that plays an essential role in regulating polyamine homeostasis by catalyzing the back-conversion of Spm to Spd. The development of many types of epithelial cancer is associated with inflammation, and disease-related inflammatory stimuli induce SMOX. MDL72527 is widely used in vitro and in vivo as an irreversible inhibitor of SMOX, but it is also potent towards N1-acetylpolyamine oxidase. Although SMOX has high substrate specificity, Spm analogues have not been systematically studied as enzyme inhibitors. Here we demonstrate that 1,12-diamino-2,11-bis(methylidene)-4,9-diazadodecane (2,11-Met2-Spm) has, under standard assay conditions, an IC50 value of 169 μM towards SMOX and is an interesting instrument and lead compound for studying polyamine catabolism.
Highlights
The biogenic polyamines spermine (Spm) and spermidine (Spd), and their diamine precursor putrescine (Put), are organic polycations present in all eukaryotic cells in μM-mM concentrations that a priori determine the diversity of their functions, many of which are vitally important [1, 2]
Disturbances of polyamine metabolism and homeostasis are associated with many diseases [1,2,3,4,5,6], but they may be most essential to cancer cells, which can have elevated requirements for polyamines
Design of a Spermine oxidase (SMOX) inhibitor of Spm origin There is a set of different strategies to design suicide inhibitors of the enzymes of amino acid metabolism
Summary
The biogenic polyamines spermine (Spm) and spermidine (Spd), and their diamine precursor putrescine (Put), are organic polycations present in all eukaryotic cells in μM-mM concentrations that a priori determine the diversity of their functions, many of which are vitally important [1, 2]. Among a family of N-substituted 3,5-diamino-1,2,4-triazoles, an efficient and specific inhibitor of SMOX, N5-(2-([1,1′-biphenyl]-4-yloxy) benzyl)-1H-1,2,4-triazole-3,5-diamine, was identified as having an IC50 value of 25 μM (the compound had an IC50 value of >200 μM towards PAOX); this compound efficiently inhibited SMOX in cell culture [14]. This is the one compound that is significantly more effective towards SMOX than PAOX. We started such investigations using 2,11-Met2-Spm (Fig. 2A) for the inhibition of SMOX
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