Inhibition of 5-lipoxygenase by substituted 3,4-dihydro-2H-1,4-thiazines.
A series of substituted 3,4-dihydro-2H-1,4-thiazines inhibit 5-lipoxygenase from rat leukocytes and exhibit submicromolar IC50 values. A novel synthesis of these compounds was developed based on the formation of hydroxymethyleneamine 13 and its cyclization to the title compounds. The dihydrothiazines have low oxidation potentials, typically E1/2 is near 0.3 V, and a representative compound reduces Fe(III)(phen)3, with k = 10(5) M-1s-1. We propose that these lipophilic compounds bind to 5-lipoxygenase and reduce the iron in the active site, thus inactivating the enzyme.
Weintraub
P M
PM
Merrell Dow Research Institute, Cincinnati, OH 45215.
Skoog
M T
MT
Nichols
J S
JS
Wiseman
J S
JS
Huber
E W
EW
Baugh
L E
LE
Farrell
A M
AM
D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D066298:In Vitro Techniques; D007975:Leukotriene B4 / Q000378:metabolism; D008054:Lipid Peroxides / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D013843:Thiazines / Q000494:pharmacology*
D008054:Lipid Peroxides; D016859:Lipoxygenase Inhibitors; D013843:Thiazines; D007975:Leukotriene B4