Identification of a novel substrate-derived spermine oxidase inhibitor

Abstract

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.

Self-Assembled Alkylated Polyamine Analogs as Supramolecular Anticancer Agents

“…The induction of SMOX has been implicated in the etiology of several epithelial cancers associated with infection and/or inflammation, including lung, colon, gastric, skin, and prostate cancers [19,20]. As Spm is a substrate of SMOX [21], it was of interest to explore the conformationally restrained HPG analogs as SMOX inhibitors. Thus, all the HPG analogs were screened for the inhibition of SMOX with respect to the established irreversible inhibitor MDL72527 with an IC 50 value of 90 µM [21].…”

“…As Spm is a substrate of SMOX [21], it was of interest to explore the conformationally restrained HPG analogs as SMOX inhibitors. Thus, all the HPG analogs were screened for the inhibition of SMOX with respect to the established irreversible inhibitor MDL72527 with an IC 50 value of 90 µM [21]. We examined the ability of the HPG analogs to directly inhibit the SMOX enzyme activity.…”

Polyamines and polyamine-metabolizing enzymes in schizophrenia: Current knowledge and concepts of therapy

“…A potentially more promising approach would be to reduce SMOX expression or activity in order to diminish the generation of hydrogen peroxide and acrolein. Indeed, it has been shown recently that targeting SMOX is neuroprotective in a model of ischemic brain damage[ 108 ]. In this context, however, two questions need to be answered: (1) How to depress SMOX activity; and (2) What would be the consequences of this?…”

“…One of these is the application of the SMOX inhibitor N -(3-{[3-(dimethylamino)propyl] amino}propyl)-8-quinolinecarboxamide, which is under consideration for anti-cancer therapy[ 107 ]. Another one is the irreversible inhibition of SMOX by use of the PAO inhibitor MDL72527 {N1,N4-(bis(2,3-butadienyl)-1,4-butanediamine)}[ 108 ]. However, the application of both enzyme inhibitors produces a number of serious side effects.…”

“…However, the application of both enzyme inhibitors produces a number of serious side effects. Furthermore, SMOX has an essential role in normal brain PA homeostasis (for review, see[ 101 , 107 , 108 ]), which might be disrupted by any kind of intervention. Thus, the use of these enzyme inhibitors for schizophrenia therapy does not appear to be viable.…”