The relationship between structure and antioxidative activity of piperidine nitroxides

Abstract

We have investigated the relationship between structure and antioxidative activity of piperidine nitroxides which were substituted by different groups at the 4-position. All of the tested piperidine nitroxides inhibited malondialdehyde (MDA) generation caused either spontaneously or by a hydroxyl free radical generation system (Fe 2þ -ascorbic acid) in homogenates of liver, heart and kidney of rats, and antagonized H 2 O 2 -induced haemolysis from rat erythrocytes in a concentration-dependent manner. The same rank was followed: Bis-(4-amino-2,2,6,6-tetramethyl piperidinooxyl) (4-BIS-Tempo) and 4-azido-2,2,6,6-tetramethyl piperidinooxyl (4-N 3 -Tempo) > 4-isothiocyanate-2,2,6,6-tetramethyl piperidinooxyl (4-ISO-Tempo), 4-2 0 ,4 0 -dinitrophenylhydrazone-2,2,6,6-tetramethyl piperidinooxyl (4-D-Tempo), 4-sulfonate-2,2,6,6-tetramethyl piperidinooxyl (4-S-Tempo) and 4-amino-2,2,6,6-tetramethyl piperidinooxyl (4-NH 2 -Tempo) > 4-acetate ester-2,2,6,6-tetramethyl piperidinooxyl (4-A-Tempo) and 4-benzoate-2,2,6,6-tetramethyl piperidinooxyl (4-B-Tempo). With the exception of 4-A-Tempo and 4-D-Tempo, the tested piperidine nitroxides inhibited superoxide anion ðO 2 À Þ release from neutrophils stimulated by zymosan. The concentration required for inhibiting O 2 À release was higher than that of inhibiting MDA formation and haemolysis. However, 4-amino-2,2,6,6-tetramethyl piperidine (4-NH 2 -TempH) and other 4-position substitutes, such as NaN 3 and isothiocyanate, had no effects on MDA formation, haemolysis or O 2 À release. The results indicated that nitroxides have a wide range of scavenging reactive oxygen species (ROS) actions. The nitroxide moiety was the essential group while the 4-position substitutes could influence the activity of nitroxides on scavenging ROS.

Effects of tempol and redox-cycling nitroxides in models of oxidative stress

“…Tempol inhibited parasite growth in the erythrocytes (Schwartz et al, 1999) and protected erythrocytes from oxidative hemolysis (Wu et al, 1997; Li et al, 2006) likely by limiting ·OH formation by iron-catalyzed metabolism of H 2 O 2 . Erythrocytes from mice infected with the malaria parasite Plasmodium berghei reduced nitroxides at an accelerated rate (imply a hypoxic or reducing environment) that was corrected by chloroquine (Deslauriers et al, 1987).…”

Chemistry and Antihypertensive Effects of Tempol and Other Nitroxides

“…It is a redox cycling agent that can metabolize superoxide anion ( ${\text{O}}_2^{\overline{·}}$) and many other ROS (Krishna et al, 1992, 1996a, 1998; Li et al, 2006). Tempol is among the most potent of the nitroxides in protecting cells and tissues from the damaging effects of ROS (Krishna et al, 1998; Li et al, 2006). The action of nitroxides to metabolize ROS is ascribed primarily to cyclic one- or two-electron transfer among three oxidation states: the oxammonium cation, the nitroxide, and the hydroxylamine (Fig.…”

“…Li et al (2006) recently compared the IC 50 values (potency) of nitroxides in protecting lipids from peroxidation by • OH [assessed from malondialdehyde (MDA) formation in tissue extracts stimulated with Fe 2+ and ascorbic acid], in protecting cells from damage by H 2 O 2 (assessed from red blood cell hemolysis by H 2 O 2 ), and in enhancing ${\text{O}}_2^{\overline{·}}$ metabolism (assessed from formazan generation by the addition of nitroblue tetrazolium to zymosan A-stimulated leukocytes). Among eight 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) derivatives, 4–bis-TEMPO was the most potent.…”

“…The nitroxide moiety has been found to be essential for full antioxidant activity, whereas substitution at the 4-position affects potency (Samuni et al, 1988, 1990a; Krishna et al, 1998; Samuni and Barenholz, 2003; Anzai et al, 2006; Li et al, 2006). Extensive studies by Mitchell, Krishna, and colleagues using physiochemical methods coupled with EPR established that the one-electron redox cycling of six-member ring nitroxides such as tempol was enhanced by their ability to undergo reversible “boat-and-chair” conformational change (Krishna et al, 1996b).…”

Mitochondrial Dysfunction and Redox Imbalance as a Diagnostic Marker of “Free Radical Diseases”

“…and stability to reduction. For example, TEMPO derivatives with different substitutes at 4-position in the ring could influence the ROS scavenging activity and time for interaction with superoxide (84).…”