5-Selenization of salicylic acid derivatives yielded isoform-specific 5-lipoxygenase inhibitors.
Low molecular weight seleno-organic compounds exhibit glutathione peroxidase (GPx)-like activity; the well-known compound ebselen is being used in clinical trials as a stroke medication. Here, we describe the facile one-step synthesis of novel 5-selenized salicylic acid derivatives using selenium tetrachloride. The products were analyzed by spectroscopic studies including (77)Se-NMR and some were subjected to X-ray structure determination. Several products were identified as selective inhibitors of the pro-inflammatory 5-lipoxygenase (LOX) but had little effect on the catalytic activity of 12/15-LOX, which has been implicated in the synthesis of anti-inflammatory mediators. Such isoform-specificity (specificity coefficient >120) has not been reported before for any seleno-organic compound. In addition, synthesis products exhibited GPx-like activity, which was higher than that of ebselen for some derivatives.
Yu
Sun-Chol
SC
Institute of Biochemistry, University Medicine Berlin-Charité, Monbijoustrasse 2, 10117 Berlin, Germany.
Kuhn
Hartmut
H
Daniliuc
Constantin-Gabriel
CG
Ivanov
Igor
I
Jones
Peter G
PG
du Mont
Wolf-Walther
WW
D000975:Antioxidants / Q000138:chemical synthesis / Q000494:pharmacology; D001393:Azoles / Q000737:chemistry; D002712:Chlorides / Q000737:chemistry*; D018360:Crystallography, X-Ray; D005978:Glutathione / Q000737:chemistry; D054833:Isoindoles; D008084:Lipoxygenase / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D008956:Models, Chemical; D016566:Organoselenium Compounds / Q000737:chemistry; D020156:Salicylic Acid / Q000737:chemistry*; D018036:Selenium Compounds / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000975:Antioxidants; D001393:Azoles; D002712:Chlorides; D054833:Isoindoles; D016859:Lipoxygenase Inhibitors; D016566:Organoselenium Compounds; D018036:Selenium Compounds; C042986:ebselen; C070974:selenium tetrachloride; D008084:Lipoxygenase; D005978:Glutathione; D020156:Salicylic Acid