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

Publisher Website
Google Scholar
Abstract
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.