Inhibition of leukocyte functions by the alkaloid isaindigotone from Isatis indigotica and some new synthetic derivatives.
The alkaloid isaindigotone (1a) and seven derivatives have been synthesized to study their influence on several leukocyte functions and the generation of inflammatory mediators. Isaindigotone (1a) was found to be a scavenger of superoxide generated either by the hypoxanthine/xanthine oxidase system or stimulated human neutrophils. Isaindigotone (1a) and its acetylated derivative (1b) also inhibited 5-lipoxygenase activity and leukotriene B(4) production in these cells, whereas none of the compounds affected degranulation. In RAW 264.7 macrophages stimulated with lipopolysaccharide, synthetic derivatives exerted higher inhibitory effects on prostaglandin E(2) (PGE(2)) and nitric oxide (NO) generation when compared with (1a). The presence of an acetoxyl group at C-4' favors the inhibition of NO and PGE(2) production, whereas the fluoro substituent at C-4' or the absence of substituents on the aromatic ring of the benzylidene unit improves the inhibition of PGE(2). Thus, this series of compounds can attenuate the production of mediators relevant to the inflammatory response.
Molina
P
P
Departamento de Química Orgánica, Facultad de Química, Universidad de Murcia, Murcia, Spain. pmolina@um.es
Tárraga
A
A
Gonzalez-Tejero
A
A
Rioja
I
I
Ubeda
A
A
Terencio
M C
MC
Alcaraz
M J
MJ
D000470:Alkaloids / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D000818:Animals; D019607:Brassicaceae / Q000737:chemistry; D002478:Cells, Cultured / Q000187:drug effects; D002855:Chromatography, Thin Layer; D015232:Dinoprostone / Q000037:antagonists & inhibitors; D016166:Free Radical Scavengers / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D018836:Inflammation Mediators / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007975:Leukotriene B4 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D015394:Molecular Structure; D009504:Neutrophils / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism; D010946:Plants, Medicinal / Q000737:chemistry*; D011799:Quinazolines; D013329:Structure-Activity Relationship; D014969:Xanthine Oxidase / Q000378:metabolism
D000470:Alkaloids; D016166:Free Radical Scavengers; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors; D011799:Quinazolines; C440668:isaindigotone; D007975:Leukotriene B4; D019001:Nitric Oxide Synthase; D014969:Xanthine Oxidase; D015232:Dinoprostone