Redox inactivation of human 15-lipoxygenase by marine-derived meroditerpenes and synthetic chromanes: archetypes for a unique class of selective and recyclable inhibitors.
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.
Cichewicz
Robert H
RH
Department of Chemistry and Biochemistry and Institute for Marine Sciences, University of California, Santa Cruz, CA 95064, USA.
Kenyon
Victor A
VA
Whitman
Stephanie
S
Morales
Nancy M
NM
Arguello
Joanne F
JF
Holman
Theodore R
TR
Crews
Phillip
P
D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism; D002839:Chromans / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D004224:Diterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D004789:Enzyme Activation; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D010084:Oxidation-Reduction; D011161:Porifera / Q000737:chemistry*
D002839:Chromans; D004224:Diterpenes; D016859:Lipoxygenase Inhibitors; D001093:Arachidonate 15-Lipoxygenase