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Novel 15-Lipoxygenase-1 Inhibitor Protects Macrophages from Lipopolysaccharide-Induced Cytotoxicity

Guo, H., Verhoek, I. C., Prins, G. G. H., van der Vlag, R., van der Wouden, P. E., van Merkerk, R., Quax, W. J., Olinga, P., Hirsch, A. K. H. & Dekker, F. J., 9-May-2019, In : Journal of Medicinal Chemistry. 62, 9, p. 4624-4637 14 p.

Research output: Contribution to journalArticleAcademicpeer-review

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-?B 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.

Original languageEnglish
Pages (from-to)4624-4637
Number of pages14
JournalJournal of Medicinal Chemistry
Volume62
Issue number9
Early online date9-Apr-2019
Publication statusPublished - 9-May-2019

    Keywords

  • SELECTIVE INHIBITORS, NITRIC-OXIDE, IN-VITRO, POTENT, ACID, ACTIVATION, IDENTIFICATION, LIPOXYGENASE, DERIVATIVES, MECHANISMS

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