Redox Inactivation of Human 15-Lipoxygenase by Marine-Derived Meroditerpenes and Synthetic Chromanes:  Archetypes for a Unique Class of Selective and Recyclable Inhibitors

• Published in: Journal of the American Chemical Society 2004-11, Vol.126 (45), p.14910-14920
• Main Authors: Cichewicz, Robert H, Kenyon, Victor A, Whitman, Stephanie, Morales, Nancy M, Arguello, Joanne F, Holman, Theodore R, Crews, Phillip
• Format: Article
• Language: English
• Subjects: Animals; Arachidonate 15-Lipoxygenase - metabolism; Biological and medical sciences; Chromans - chemistry; Chromans - isolation & purification; Chromans - pharmacology; Diterpenes - chemistry; Diterpenes - isolation & purification; Diterpenes - pharmacology; Enzyme Activation; General and cellular metabolism. Vitamins; Humans; Lipoxygenase Inhibitors - chemistry; Lipoxygenase Inhibitors - isolation & purification; Lipoxygenase Inhibitors - pharmacology; Magnetic Resonance Spectroscopy; Medical sciences; Oxidation-Reduction; Pharmacology. Drug treatments; Porifera - chemistry
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja046082z

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.