Redox Inactivation of Human 15-Lipoxygenase by Marine-Derived Meroditerpenes and Synthetic Chromanes: Archetypes for a Unique Class of Selective and Recyclable Inhibitors
| Autor: | Joanne F. Arguello, Robert H. Cichewicz, Victor Kenyon, Nancy M. Morales, Theodore R. Holman, Phillip Crews, Stephanie Whitman |
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| Rok vydání: | 2004 |
| Předmět: |
Magnetic Resonance Spectroscopy
Stereochemistry Biochemistry Redox Catalysis chemistry.chemical_compound Lipoxygenase Colloid and Surface Chemistry Animals Arachidonate 15-Lipoxygenase Humans Moiety Lipoxygenase Inhibitors Chromans chemistry.chemical_classification biology Chemistry Biological activity General Chemistry Porifera Enzyme Activation Enzyme Enzyme inhibitor biology.protein Diterpenes Pharmacophore Diterpene Oxidation-Reduction |
| Zdroj: | Journal of the American Chemical Society. 126:14910-14920 |
| ISSN: | 1520-5126 0002-7863 |
| Popis: | The selective inhibition of human 15-lipoxygenase (15-hLO) could serve as a promising therapeutic target for the prevention of atherosclerosis. A screening of marine sponges revealed that crude extracts of Psammocinia sp. exhibited potent 15-hLO inhibitory activity. Bioassay-guided fractionation led to the isolation of chromarols A-E (8-12) as potent and selective inhibitors of 15-hLO. An additional 22 structurally related compounds, including meroditerpenes from the same Psammocinia sp. (3, 4, 13-16) and our pure compound repository (17, 18), commercially available tocopherols (19-24), and synthetic chromanes (25-32), were evaluated for their ability to inhibit human lipoxygenases. The 6-hydroxychromane moiety found in chromarols A-D was identified as essential for the selective redox inhibition of 15-hLO. Furthermore, the oxidized form of the 6-hydroxychromane could be reduced by ascorbate, suggesting a potential regeneration pathway for these inhibitors in the body. This pharmacophore represents a promising paradigm for the development of a unique class of recyclable 15-hLO redox inhibitors for the treatment of atherosclerosis. |
| Databáze: | OpenAIRE |
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