Potent inhibition of human 5-lipoxygenase and microsomal prostaglandin E2 synthase-1 by the anti-carcinogenic and anti-inflammatory agent embelin

Perspective of microsomal prostaglandin E2 synthase-1 as drug target in inflammation-related disorders

“…mPGES-1 as target of these NPs may provide a basis for their antiinflammatory properties and rationalize their use in folk medicine as remedy for treatment of inflammatory disorders. Among these plant-derived mPGES-1 inhibitors are prominent antiinflammatory and anti-tumoral compounds like the polyphenol curcumin from turmeric [86], epigallocatechin-3-gallate (EGCG) from green tea [87], the acylphloroglucinol hyperforin from St. John´s wort [66] and garcinol from Garcinia indica [88], triterpene acids from frankincense (e.g., tirucallic acids, lupeolic acids, boswellic acids,) [89,90], the diterpenoids carnosol and carnosic acid from Salvia officinalis [91], and the quinone embelin from Embelia ribes [92]. All of them inhibit mPGES-1 in cell-free assays in the submicromolar range (Table 1).…”

Targeting V-ATPase in primary human monocytes by archazolid potently represses the classical secretion of cytokines due to accumulation at the endoplasmic reticulum

“…Platelets and peripheral blood mononuclear cells (PBMC) were isolated by dextran sedimentation and centrifugation on LSM 1077 lymphocyte separation medium (PAA Laboratories, Pasching, Germany), as described [19,20]. To obtain monocytes, PBMC were collected, washed two times with cold PBS, and monocytes were separated by adherence for 1.5 h at 37 °C to culture flasks (210 7 cells/mL RPMI 1640 medium containing 2 mM L-glutamine and 100 U/mL penicillin plus 100 µg/mL streptomycin).…”

Novel series of benzoquinones with high potency against 5-lipoxygenase in human polymorphonuclear leukocytes

“…Compound 17d, at a concentration of 10 mM, inhibited 5-LO by only 43.9%. Note that none of the compounds was superior over parental 2 (IC 50 ¼ 0.06 mM) [13], in this respect. Therefore, a relationship between the length of the n-alkyl chain and the 5-LO inhibitory potential of 3-substituted 2,5-dihydroxy-1,4-benzoquinones is apparent, where the C11-n-alkyl residue is seemingly optimal.…”

“…1), a naturally occurring 1,4-benzoquinone from Embelia ribes, that dually inhibits 5-LO as well as microsomal prostaglandin E 2 synthase (mPGES)-1 but does not interfere with 12/15-LOs, cytosolic phospholipase (PL)A 2 or cyclooxygenase (COX) enzymes [13]. In a parallel study we synthesized and characterized a series of related 2,5-dihydroxylated 1,4-benzoquinones with various lipophilic and bulky alkyl-or aryl-substituents in 3-position [14], exemplified by 3-((decahydronaphthalen-6-yl)methyl)-2,5-dihydroxycyclohexa-2,5-diene-1,4-dione (compound 2a, Fig.…”

“…The simple structure and good potency of 2 and 2a with IC 50 values in the submicromolar range stimulated us to systematically modify the structure of 2 and thus, to improve the inhibitory potential as well as to investigate SARs. In particular, we aimed at improving the 5-LO inhibitory potential in intact cells, because the potency of 2 in cell-free assays (IC 50 ¼ 0.06 mM) was 13-to 33-fold higher than in cell-based test systems (0.8e2 mM) [13].…”