Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 14, Issue 12, Pages 4295-4301Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2006.01.057
Keywords
lipoxygenase; baicalein; apigenin; flavonoids; kinetics; reductive inhibition; IC50
Funding
- NIGMS NIH HHS [GM 56062-06] Funding Source: Medline
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Lipoxygenases (LO) have been implicated in asthma, immune disorders, and various cancers and as a consequence, there is great interest in isolating selective LO isozyme inhibitors. Currently, there is much use of baicalein as a selective human platelet 12-LO (12-hLO) inhibitor, however, our current steady-state inhibition data indicate that baicalein is not selective against 12-hLO versus human reticulocyte 15-LO-1 (15-hLO-1) (15/12 = 1.3), in vitro. However, in the presence of detergents baicalein is slightly more selective (15/12 = 7) as seen by the steady-state inhibition kinetics, which may imply greater selectivity in a cell-based assay but has yet to be proven. The mechanism of baicalein inhibition of 15-hLO-1 is reductive, which molecular modeling suggests is through direct binding of the catecholic moiety of baicalein to the iron. A structurally related flavonoid, apigenin, is not reductive, however, molecular modeling suggests a hydrogen bond with Thr591 may account for its inhibitor potency.
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