Synthesis, antioxidant properties, biological activity and molecular modelling of a series of chalcogen analogues of the 5-lipoxygenase inhibitor DuP 654.
2-Phenylsulfenyl- (1b), 2-phenylselenenyl- (1c) and 2-phenyltellurenyl-1-naphthol (1d) were prepared and their antioxidative properties evaluated in comparison with 2-benzyl-1-naphthol (1a; DuP 654). 2-Phenyltellurenyl-1-naphthol had a significantly lower (1.00 V versus SCE) oxidation potential than the other three compounds (1.24, 1.27 and 1.25 V, respectively, versus SCE for compounds 1a, 1b and 1c) as determined by cyclic voltammetry. In contrast to the other materials, compound 1d was able to catalyze the reduction of hydrogen peroxide in the presence of thiols as stoichiometric reducing agents. The organotellurium compound was also the most efficient inhibitor of azo-initiated peroxidation of linoleic acid in a two-phase model system. Ab initio geometry optimization at the 3-21G(*) level revealed infinitesimal changes in the molecular conformations of the carbon, sulfur, selenium and tellurium analogues. As judged by their ability to inhibit stimulated LTB4 biosynthesis in human neutrophils, compounds 1a-1d all turned out to be highly potent 5-lipoxygenase inhibitors with IC50-values ranging from 0.40 microM for 2-benzyl-1-naphthol (1a) to 0.063 microM for 2-phenyltellurenyl-1-naphthol (1d).
Engman
L
L
Uppsala University, Department of Organic Chemistry, Sweden.
Stern
D
D
Frisell
H
H
Vessman
K
K
Berglund
M
M
Ek
B
B
Andersson
C M
CM
D000975:Antioxidants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006801:Humans; D007975:Leukotriene B4 / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009284:Naphthols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D012643:Selenium / Q000737:chemistry; D013329:Structure-Activity Relationship; D013455:Sulfur / Q000737:chemistry; D013691:Tellurium / Q000737:chemistry
D000975:Antioxidants; D016859:Lipoxygenase Inhibitors; D009284:Naphthols; D007975:Leukotriene B4; D013455:Sulfur; C061316:2-(phenylmethyl)-1-naphthol; D012643:Selenium; D013691:Tellurium