Inhibition of human neutrophil 5-lipoxygenase activity by gingerdione, shogaol, capsaicin and related pungent compounds

Abstract

A series of structurally related pungent natural products including capsaicin, gingerol, and gingerdione among others were evaluated and found to be potent inhibitors of 5-HETE biosynthesis in intact human leukocytes, with IC50 values of 100 and 15 μM for capsaicin and gingerdione, respectively. Several compounds within this series were also found to inhibit PGE2 formation, with the most potent being gingerdione (IC50 = 18 μM). These and other data indicate that members of the capsaicin/gingerol family of pungent compounds can act as dual inhibitors of arachidonic acid metabolism, which could account in part for the antiinflammatory and analgesic properties of compounds within this group.Capsaicin (entry 1) is representative of a family of structurally analogous natural products which impart a pungent taste to the plant tissues from which they are isolated (1). These compounds all bear a 4-hydroxy-3-methoxyphenyl moiety which is a major structural determinant for the flavoring properties of these compounds. Included in this group of compounds is [6]-gingerol (entry 2), shogaol (entry 3), gingerdione (entry 4), and the paradols, represented by entry 6, all of which were isolated from ginger root or closely related species (2,3). Members of a slightly different class of natural products, the diarylheptagoids, also belong to this family of pungent compounds and are represented by curcumin (entry 7 (4)) and the yakuchinones (5).In addition to their flavoring properties, many of the aforementioned compounds also possess a range of interesting pharmacological properties (6,7). Most noteworthy is the antiinflammatory action of curcumin, which is currently in clinical trials in India (8), and the antiinflammatory/analgesic properties of gingerol and shogaol (6). Recently, we disclosed that curcumin and the related diarylheptanoids were excellent dual inhibitors of arachidonic acid metabolism (9), which could account for their antiinflammatory effects.The structural relationship of these compounds prompted us to also look at capsaicin and some other pungent natural products for similar activity. As was the case with the diarylheptanoids (10), members of the gingerol family have been reported in the literature to inhibit prostaglandin synthetase (2). We can now report that some of these compounds are also potent inhibitors of 5-hydroxyeicosatetraenoic acid (5-HETE) formation in intact human neutrophils as well as inhibitors of cyclooxygenase, categorizing them as functional dual inhibitors of arachidonic acid metabolism.