Natural Product Libraries
Natural products are an unsurpassed source of chemical diversity and are an ideal starting point for any screening program for pharmacologically active small molecules. Historically, natural products have been the most successful source of new drugs. We have a growing natural product library with purified natural products of known structure, including many compounds from ethnopharma-cological and medicinal plant research. Moreover, in collaboration with researchers worldwide we screen characterized plant extracts for further purification, isolation and structure eluciation.
Gingerols and Shogaols as broad scaffolds to target PLA2
Ginger preparations as they are used in Traditional Chinese Medicine or Asian phytotherapy have been shown to inhibit inflammation in different animal models and in clinical observations. In a study published in Journal of Immunology (J Immunol. 2011 Oct 15;187(8):4140-50.) we show that gingerols and shogaols not only inhibit leukotriene biosynthesis but also target phospholipases A2, thus providing an example of polypharmacology. The natural ginger phenylpropanoid scaffold (Figure) may be exploited to generate more stable and potent PLA2 inhibitors.
Ginger phenylpropanoids (ACS chemistry for life)
ABSTRACT of STUDY
The rhizome of ginger (Zingiber officinale) is employed in Asian traditional medicine to treat mild forms of rheumatoid arthritis and fever. We have profiled ginger constituents for robust effects on proinflammatory signaling and cytokine expression in a validated assay using human whole blood. Independent of the stimulus used (LPS, PMA, anti-CD28 Ab, anti-CD3 Ab, and thapsigargin), ginger constituents potently and specifically inhibited IL-1β expression in monocytes/macrophages. Both the calcium-independent phospholipase A(2) (iPLA(2))-triggered maturation and the cytosolic phospholipase A(2) (cPLA(2))-dependent secretion of IL-1β from isolated human monocytes were inhibited. In a fluorescence-coupled PLA(2) assay, most major ginger phenylpropanoids directly inhibited i/cPLA(2) from U937 macrophages, but not hog pancreas secretory phospholipase A(2). The effects of the ginger constituents were additive and the potency comparable to the mechanism-based inhibitor bromoenol lactone for iPLA(2) and methyl arachidonyl fluorophosphonate for cPLA(2), with 10-gingerol/-shogaol being most effective. Furthermore, a ginger extract (2 μg/ml) and 10-shogaol (2 μM) potently inhibited the release of PGE(2) and thromboxane B2 (>50%) and partially also leukotriene B(4) in LPS-stimulated macrophages. Intriguingly, the total cellular arachidonic acid was increased 2- to 3-fold in U937 cells under all experimental conditions. Our data show that the concurrent inhibition of iPLA(2) and prostanoid production causes an accumulation of free intracellular arachidonic acid by disrupting the phospholipid deacylation-reacylation cycle. The inhibition of i/cPLA(2), the resulting attenuation of IL-1β secretion, and the simultaneous inhibition of prostanoid production by common ginger phenylpropanoids uncover a new anti-inflammatory molecular mechanism of dietary ginger that may be exploited therapeutically.
INFLAMMATION, CLINICAL, HEALTH, MECHANISM OF ACTION, PHYTOTHERAPY, SEXUAL DISFUNCTION, DIET, PATHOLOGY, AGING, DISEASE, NATURE, NATURAL,