Exploring the activity of polyamine analogues on polyamine and spermine oxidase: methoctramine, a potent and selective inhibitor of polyamine oxidase

Abstract

2019) Exploring the activity of polyamine analogues on polyamine and spermine oxidase: methoctramine, a potent and selective inhibitor of polyamine oxidase, Journal of Enzyme Inhibition and Medicinal Chemistry, 34:1, 740-752, ABSTRACT Fourteen polyamine analogues, asymmetric or symmetric substituted spermine (1-9) or methoctramine (10-14) analogues, were evaluated as potential inhibitors or substrates of two enzymes of the polyamine catabolic pathway, spermine oxidase (SMOX) and acetylpolyamine oxidase (PAOX). Compound 2 turned out to be the best substrate for PAOX, having the highest affinity and catalytic efficiency with respect to its physiological substrates. Methoctramine (10), a well-known muscarinic M 2 receptor antagonist, emerged as the most potent competitive PAOX inhibitor known so far (K i ¼ 10 nM), endowed with very good selectivity compared with SMOX (K i ¼1.2 lM vs SMOX). The efficacy of methoctramine in inhibiting PAOX activity was confirmed in the HT22 cell line. Methoctramine is a very promising tool in the design of drugs targeting the polyamine catabolism pathway, both to understand the physio-pathological role of PAOX vs SMOX and for pharmacological applications, being the polyamine pathway involved in various pathologies. ARTICLE HISTORY

Structure of human spermine oxidase in complex with a highly selective allosteric inhibitor

“…Furthermore, the potency of the hSMOX inhibitor chlorhexidine measured in our HTS assay (IC 50 = 1.9 µM) is similar to the value reported for the murine SMOX enzyme ( K i = 3.8 ± 0.2 µM; Supplementary Fig. 8 ) 50 . Based on this assay, we carried out a high-throughput screening campaign searching for inhibitors of hSMOX against a diverse compound collection.…”

“…9). This observed selectivity against hPAOX and LSD1 differentiates JNJ-1289 from other molecules reported in the literature that inhibit these enzymes 27,28,50,51 . Thermal-shift analysis of hSMOX in the presence of JNJ-1289 or DMSO revealed robust stabilization of the protein (ΔT m = 11.3 °C) by JNJ-1289, consistent with JNJ-1289 binding to hSMOX in a specific manner (Fig.…”

Bovine Serum Amine Oxidase and Polyamine Analogues: Chemical Synthesis and Biological Evaluation Integrated with Molecular Docking and 3-D QSAR Studies

“…Furthermore, as 3 , 11 , 13 , and 20 were previously shown to be substrates both of spermine oxidase (SMOX) and of acetylpolyamine oxidase (APAOX), it cannot be excluded that 8 and 10 and/or other BSAO analogues might be substrate/s of these enzymes, which, producing cytotoxic reaction products, could potentiate the effect of BSAO and be useful/synergic in the anticancer therapy. , …”

Biochemical and pathophysiological properties of polyamines

“…The docking revealed a distinction in the mode of binding of both activators and inhibitors with the enzyme via Asp211 and Tyr204. These results may be useful for structure-based drug design (Di Paolo et al 2019). Dysregulation of epigenetic control of gene expression is a common feature in the initiation and progression of cancer.…”

“…Generally, the activation of PA catabolism is associated with the formation of cytotoxic products and cancer cells death (Murray-Stewart et al 2018b). Several compounds are known to induce PA catabolic enzymes (Di Paolo et al 2019). Syatkin et al (2020) report the investigation of structure-activity relationship of polyamine-targeted synthetic compounds from different chemical groups.…”