Identification of a novel substrate-derived spermine oxidase inhibitor

• Published in: Actanaturae Vol. 12; no. 3; pp. 140 - 144
• Main Authors: Dunston, T. T., Khomutov, M. A., Gabelli, S. B., Stewart, T. M., Foley, J. R., Kochetkov, S. N., Khomutov, A. R., Casero Jr, R. A.
• Format: Journal Article
• Language: English
• Published: A.I. Gordeyev 01-07-2020
• ISSN: 2075-8251
• DOI: 10.32607/actanaturae.10992

Homeostasis of the biogenic polyamines spermine (Spm) and spermidine (Spd), present in M-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 M towards SMOX and is an interesting instrument and lead compound for studying polyamine catabolism.