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Novel 15-Lipoxygenase-1 Inhibitor Protects Macrophages from Lipopolysaccharide-Induced Cytotoxicity.
Guo, Hao Verhoek, Iris C Prins, Gerian G H van der Vlag, Ramon van der Wouden, Petra E van Merkerk, Ronald Quax, Wim J Olinga, Peter Hirsch, Anna K H Dekker, Frank J
Guo, Hao
Verhoek, Iris C
Prins, Gerian G H
van der Vlag, Ramon
van der Wouden, Petra E
van Merkerk, Ronald
Quax, Wim J
Olinga, Peter
Hirsch, Anna K H
Dekker, Frank J
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2019-04-19
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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.
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J Med Chem. 2019;62(9):4624-4637. doi:10.1021/acs.jmedchem.9b00212.
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en
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1520-4804
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Attribution-NonCommercial-ShareAlike 4.0 International