Polyamines are abundant and ubiquitous compounds that are essential for cellular growth and development. Within the central nervous system, the major intracellular polyamines (spermine and spermidine) are stored in astrocytes and when released, have the potential to act as free radical scavengers in response to neuronal damage. Spermine catabolism is mediated primarily by spermine oxidase (SMOX), a highly inducible flavin-dependent amine oxidase that is upregulated in a variety of cell types during ischemic, excitotoxic, and inflammatory states. In addition to the loss of radical scavenging capabilities associated with spermine depletion, catabolism of spermine by SMOX results in the production of toxic byproducts, including H2O2 and acrolein, a highly toxic aldehyde with the ability to conjugate DNA and inactivate vital cellular proteins. Despite extensive evidence implicating SMOX as a key enzyme contributing to neuronal pathology, the lack of potent and selective inhibitors has significantly impeded investigation of SMOX as a therapeutic target. We recently conducted virtual and physical screening assays of our in-house proprietary compound library to identify a series of hit compounds with inhibitory activity against SMOX. A synthetic route for derivatization of selected hit compounds was developed for the generation of a small compound library with a focus on (1) variation in alkyl chain length & introduction of structural constraints, (2) bioisosteric replacement, (3) substitution of alternative electron withdrawing groups. We have now identified potent and highly selective SMOX inhibitors with IC50 values as low as 231.7 nM that represent the most potent SMOX inhibitors discovered to date. We hypothesize that these selective SMOX inhibitors will be useful as chemical probes to further elucidate the impact of polyamine catabolism on mechanisms of neuronal injury. In addition, inhibition of SMOX may represent a novel therapeutic target for the prevention and treatment of neuronal injury and other diseases.

Synthesis and derivatization of novel small-molecule inhibitors of spermine oxidase

ACS Spring 2022

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