Suppression of leukotriene B4 and tumour necrosis factor α release in acute inflammatory responses by novel prenylated hydroquinone derivatives

Abstract

A series of prenyl hydroquinone derivatives synthesized as structural analogs of marine products were tested for their effects on inflammatory responses in vitro and in vivo. 2-Prenyl-1,4-hydroquinone (H1), 2-diprenyl-1,4-hydroquinone (H2), 2-triprenyl-1,4-hydroquinone (H3) and 2-tetraprenyl-1,4-hydroquinone (H4) scavenged reactive oxygen species and inhibited 5-lipoxygenase (5-LO) activity in human neutrophils. The inhibition of 5-LO activity was demonstrated in vivo in the mouse air pouch injected with zymosan and arachidonic acid-induced ear inflammation. The four compounds suppressed the production of tumour necrosis factor alpha (TNFalpha) in J774 cells stimulated with lipopolysaccharide (LPS) and also in vivo in the mouse air pouch injected with zymosan. In addition, all prenyl-hydroquinones inhibited the release of nitrite and PGE2 in LPS-stimulated J774 cells, without direct effects on cyclo-oxygenase-1 (COX-1), cyclo-oxygenase-2 (COX-2) or inducible nitric oxide synthase (iNOS) activities in several cell-free systems. The reduction in the length of the lateral chain in prenyl-hydroquinones (1-4 isoprene units) with respect to their marine analogs (7-8 isoprene units) has improved the anti-inflammatory activity of this class of compounds. Marine natural products may be a model to design new anti-inflammatory agents.

Chemical defence by mono-prenyl hydroquinone in a freshwater ciliate, Spirostomum ambiguum

“…The biosynthesis of these compounds is mixed, with the prenylated portion of 1-9 isoprene units that derives from the mevalonate pathway, and the hydroquinone moiety that derives from shikimic acid (Scheepers et al, 2006). It is known that some prenylated hydroquinones play an important role in many biological processes including cellular respiration, photosynthesis and electron transport, but anticancer, antimutagenic, antimicrobial and anti-inflammatory properties have been also described for a number of these compounds (De Rosa et al, 1994;Terencio et al, 1998;Yang et al, 2007;Baby & Sujatha, 2011). Furthermore, an ecological role was suggested for some prenylated hydroquinones, which have been reported to exert a defensive action against predators (Park et al, 1992;Sladic & Gašic, 2006).…”

Effect of imidazo[1,2-α]pyrimidine derivatives on leukocyte function

“…Elastase activity was estimated in supernatants by fluorescence increase due to hydrolysis of rhodamine 110 bispeptide sustrate. Myeloperoxidase activity was determined in supernatants as previously described [14]. Possible direct inhibitory effects on elastase or myeloperoxidase activities were also assessed.…”

Marine Polyprenylated Hydroquinones, Quinones, and Chromenols with Inhibitory Effects on Leukotriene Formation

“…Additionally, synthetic prenyl hydroquinones, with chain lengths ranging from one to four prenyls [15], showed higher anti-inflammatory activities than those of the natural analogues bearing seven and eight prenyl groups. It seems that fewer prenyl moieties enhance the antiinflammatory activity of the metabolites due to changes in lipophilicity and their ability to anchor more efficiently on the membrane so as to access the site of leukotriene biosynthesis [32].…”

“…In the past, the extracts of several Ircinia species have been found to exert a number of biological activities, which have largely been attributed to their main constituents such as the polyprenyl benzoquinones and polyprenyl hydroquinones [8 ± 14]. Biological studies conducted on several 2'-polyprenyl-1',4'-hydroquinones isolated from the sponge I. spinosula and analogues of these metabolites showed them to be effective inhibitors of phospholipase A 2 [10], and to exert an interesting antiinflammatory action through inhibition of 5-lipoxygenase (5-LOX) [15]. Metabolites structurally related to natural products with significant anti-inflammatory activities have also been reported from the brown alga T. atomaria [16 ± 18].…”