Bioorganic & Medicinal Chemistry 2008-04-15

Inhibition of 15-lipoxygenase-catalysed oxygenation of arachidonic acid by substituted benzoic acids.

Wendy R Russell, Lorraine Scobbie, Garry G Duthie, Andrew Chesson

Index: Bioorg. Med. Chem. 16 , 4589-93, (2008)

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Abstract

Elevated levels of phospholipases, prostaglandin synthases and lipoxygenases in colonic cells at various stages of malignancy indicate a strong link between dietary lipids and colon cancer. Lipoxygenase-catalysed arachidonic acid metabolism plays a key role in colorectal carcinogenesis and has the potential to be modulated by phenolic compounds. Plant-based foods are rich sources of phenolic compounds and in the human colon they are predominantly available as simple phenolics such as the benzoic acids. Benzoic acids were determined in faecal waters from four volunteers consuming a western-style diet. Structure-activity relationships were established for the lipoxygenase-catalysed oxygenation of arachidonic acid using an oxygen electrode. All compounds studied inhibited this reaction (21-73%; p<0.001) and many of the structural features could be rationalised by computational modelling. No correlation was observed with the ability to act as reductants, supporting the hypothesis that their mode of inhibition may not be by a direct redox effect on the non-haem iron.