Abstract
Various mechanisms for regulated cell death include the formation of oxidative mediators such as lipid peroxides and nitric oxide (NO). In this respect, 15-lipoxygenase-1 (15-LOX-1) is a key enzyme that catalyzes the formation of lipid peroxides. The actions of these peroxides are interconnected with nuclear factor-κB signaling and NO production. Inhibition of 15-LOX-1 holds promise to interfere with regulated cell death in inflammatory conditions. In this study, a novel potent 15-LOX-1 inhibitor, 9c (i472), was developed and structure-activity relationships were explored. In vitro, this inhibitor protected cells from lipopolysaccharide-induced cell death, inhibiting NO formation and lipid peroxidation. Thus, we provide a novel 15-LOX-1 inhibitor that inhibits cellular NO production and lipid peroxidation, which set the stage for further exploration of these mechanisms.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Arachidonate 15-Lipoxygenase / chemistry
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Arachidonate 15-Lipoxygenase / metabolism
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Catalytic Domain
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Gene Expression / drug effects
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Indoles / chemical synthesis
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Indoles / metabolism
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Indoles / pharmacology*
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Lipid Peroxidation / drug effects
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Lipopolysaccharides / pharmacology
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Lipoxygenase Inhibitors / chemical synthesis
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Lipoxygenase Inhibitors / metabolism
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Lipoxygenase Inhibitors / pharmacology*
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Mice
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Molecular Docking Simulation
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Molecular Structure
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NF-kappa B p50 Subunit / antagonists & inhibitors
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Nitric Oxide / antagonists & inhibitors
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Nitric Oxide Synthase Type II / genetics
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Oxidative Stress / drug effects
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Protective Agents / chemical synthesis
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Protective Agents / metabolism
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Protective Agents / pharmacology*
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Protein Binding
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RAW 264.7 Cells
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Rabbits
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Signal Transduction / drug effects
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Structure-Activity Relationship
Substances
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Indoles
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Lipopolysaccharides
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Lipoxygenase Inhibitors
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NF-kappa B p50 Subunit
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Protective Agents
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Nfkb1 protein, mouse
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Nitric Oxide
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Arachidonate 15-Lipoxygenase
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Nitric Oxide Synthase Type II
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Nos2 protein, mouse