Development of Irreversible Inactivators of Spermine Oxidase and &lt;i&gt;N&lt;/i&gt;&lt;sup&gt;1&lt;/sup&gt;-Acetylpolyamine Oxidase

Moriya, Shigeki; Miura, Toshiyuki; Takao, Koichi; Sugita, Yoshiaki; Samejima, Keijiro; Hiramatsu, Kyoko; Kawakita, Masao

doi:10.1248/bpb.b13-00913

Cited by 6 publications

(4 citation statements)

References 17 publications

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“…Unfortunately, most of the mammalian PAOX and SMOX inhibitors currently available, suffer from poor selectivity, and overcoming this problem still remains an important goal for the development of novel pharmacological tools. SMOX and PAOX inhibitors are generally PA analogues 33 , such as the irreversible and “well-known” MDL 72527 ( N1,N 4 -bis(2,3-butadienyl)-1,4-butanediamine) 34 ( K i =20 and 63 μM, for purified murine PAOX and SMOX respectively) 33 and other butadienyl-spermidine derivatives with improved potency with respect to MDL 72527 35 . Interestingly, some guanidine-containing derivatives have also shown promising inhibitory activity towards PAOX and SMOX.…”

Section: Introductionmentioning

confidence: 99%

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

Paolo

Cervelli

Mariottini

et al. 2019

Journal of Enzyme Inhibition and Medicinal Chemistry

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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

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Section: Introductionmentioning

confidence: 99%

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

Paolo

Cervelli

Mariottini

et al. 2019

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…In the vitreous of patients with PDR, the concentration of the polyamine spermine, a precursor of ACR in the polyamine catabolic pathway, was found to be 15 times higher than in control subjects [74]. In a mouse model of diabetes, treatment with MDL 72,527, a dual inhibitor of SMOX and APAO [75], significantly reduced the accumulation of retinal FDP-Lys and prevented neurophysiological dysfunction and neurodegeneration [76]. These findings suggested that both lipoxidation and the dysregulation of the polyamine system could contribute to the buildup of FDP-Lys in the diabetic retina.…”

Section: αβ-Unsaturated Aldehydes 221 Acroleinmentioning

confidence: 99%

Aldehyde Dehydrogenase and Aldo-Keto Reductase Enzymes: Basic Concepts and Emerging Roles in Diabetic Retinopathy

et al. 2023

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Diabetic retinopathy (DR) is a complication of diabetes mellitus that can lead to vision loss and blindness. It is driven by various biochemical processes and molecular mechanisms, including lipid peroxidation and disrupted aldehyde metabolism, which contributes to retinal tissue damage and the progression of the disease. The elimination and processing of aldehydes in the retina rely on the crucial role played by aldehyde dehydrogenase (ALDH) and aldo-keto reductase (AKR) enzymes. This review article investigates the impact of oxidative stress, lipid-derived aldehydes, and advanced lipoxidation end products (ALEs) on the advancement of DR. It also provides an overview of the ALDH and AKR enzymes expressed in the retina, emphasizing their growing importance in DR. Understanding the relationship between aldehyde metabolism and DR could guide innovative therapeutic strategies to protect the retina and preserve vision in diabetic patients. This review, therefore, also explores various approaches, such as gene therapy and pharmacological compounds that have the potential to augment the expression and activity of ALDH and AKR enzymes, underscoring their potential as effective treatment options for DR.

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“…The active site information of the polyamine oxidizing enzymes, PAOX and SMOX, were reported by the research for their substrate activities of polyamine analogues [8–10]. These data suggested that both enzymes having substrate recognition site with two anionic centers with relatively large hydrophobic regions.…”

Section: Introductionmentioning

confidence: 98%

N1-Nonyl-1,4-diaminobutane ameliorates brain infarction size in photochemically induced thrombosis model mice

Masuko

Takao

Samejima

et al. 2018

Neuroscience Letters

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Inhibitors for polyamine oxidizing enzymes, spermine oxidase (SMOX) and N-acetylpolyamine oxidase (PAOX), were designed and evaluated for their effectiveness in a photochemically induced thrombosis (PIT) mouse model. N-Nonyl-1,4-diaminobutane (C9-4) and N-tridecyl-1,4-diaminobutane (C13-4) competitively inhibited the activity of PAOX and SMOX in a manner comparable to N,N-bis(2,3-butadienyl)-1,4-butanediamine (MDL72527), an irreversible inhibitor of both enzymes. The two compounds were then tested for their effects in the PIT model. Both intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) administration of C9-4 decreased infarct volumes significantly. By contrast, C13-4 reduced the volume of brain infarction by i.c.v. administration, but no reduction was observed after i.p. administration. C9-4 administered by i.p. injection reduced the volume of brain infarction significantly at doses of more than 3 mg/kg, and the dosage of 5 mg/kg or 10 mg/kg demonstrated the most potent effect and were more effective than equivalent doses of the other inhibitors such as MDL72527 and N-benzylhydroxylamine. I.P. injection of 5 mg/kg of C9-4 provided a therapeutic time window of longer than 12 h. This report demonstrates that C9-4 is a potent inhibitor of the polyamine oxidizing enzymes and is useful lead compound for candidate drugs with a long therapeutic time window, to be used in the treatment of ischemic stroke.

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Development of Irreversible Inactivators of Spermine Oxidase and <i>N</i><sup>1</sup>-Acetylpolyamine Oxidase

Cited by 6 publications

References 17 publications

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

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

Aldehyde Dehydrogenase and Aldo-Keto Reductase Enzymes: Basic Concepts and Emerging Roles in Diabetic Retinopathy

N1-Nonyl-1,4-diaminobutane ameliorates brain infarction size in photochemically induced thrombosis model mice

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