Pyridine and pyrimidine analogs of acetaminophen as inhibitors of lipid peroxidation and cyclooxygenase and lipoxygenase catalysis

Abstract

Herein we report an investigation of the efficacy of pyridine and pyrimidine analogs of acetaminophen (ApAP) as peroxyl radical-trapping antioxidants and inhibitors of enzyme-catalyzed lipid peroxidation by cyclooxygenases (COX) and lipoxygenases (LOX). In inhibited autoxidations we find that ApAP, the common analgesic and antipyretic agent, is a very good antioxidant with a rate constant for reaction with peroxyl radicals (kinh = 5 × 105 M−1 s−1) that is higher than many widely-used phenolic antioxidants, such as the ubiquitous butylated hydroxytoluene (BHT). This reactivity is reduced substantially upon incorporation of nitrogen into the phenolic ring, owing to an increase in the O–H bond dissociation enthalpy of pyridinols and pyrimidinols with respect to phenols. Incorporation of nitrogen into the phenolic ring of ApAP was also found to decrease its efficacy as an inhibitor of prostaglandin biosynthesis by ovine COX-1 (oCOX-1). This is explained on the basis of an increase in its oxidation potential and its reduced reactivity as a reducing co-substrate of the peroxidase protoporphyrin. In contrast, the efficacy of ApAP as an inhibitor of lipid hydroperoxide biosynthesis by soybean LOX-1 (sLOX-1) increased upon incorporation of nitrogen into the ring, suggesting a different mechanism of inhibition dependent on the acidity of the phenolic O–H which may involve chelation of the catalytic non-heme iron atom. The greater stability of the 3-pyridinols and 5-pyrimidinols to air oxidation as compared to phenols allowed us to evaluate some electron-rich pyridinols and pyrimidinols as inhibitors of oCOX-1 and sLOX-1. While the pyridinols had the best combination of activities as antioxidants and inhibitors of oCOX-1 and sLOX-1, they were found to be more toxic than ApAP in preliminary assays in human hepatocellular carcinoma (HepG2) cell culture. The pyrimidinols, however, were up to 17-fold more reactive to peroxyl radicals and up to 25-fold better inhibitors of prostaglandin biosynthesis than ApAP, with similar cytotoxicities to HepG2 cells at high levels of exposure.

An oxysterol biomarker for 7-dehydrocholesterol oxidation in cell/mouse models for Smith-Lemli-Opitz syndrome

“…An unidentifi ed peak at retention time 5.45 min in our previously published chromatogram of a 7-DHC free radical oxidation mixture was confi rmed to be epox- tests and in studies of neuronal oxidative stress (63)(64)(65)(66), and experiments were therefore carried out with SLOS HFs to assess the potential of these antioxidants to reduce the levels of oxysterols. SLOS fi broblasts in lipid-defi cient serum were incubated for 5 days in the absence or presence of 10 M antioxidant 3 ( Fig.…”

“…The precise mechanism by which antioxidants attenuate the formation of 7-DHC oxysterols has not been established. Indeed, they could inhibit both the free radical chain mechanism as well as oxygenase enzymes that operate via higher valence metals ( 65,71,72 ). But regardless of the mechanism by which the pyrimidinol antioxidant studied here exerts its effect, the net result is a reduction of formation of toxic oxysterol products.…”

The antioxidant properties of salicylate derivatives: A possible new mechanism of anti-inflammatory activity

“…In addition to single electron transfer, the ability of compounds 1-7 to effect hydrogen atom transfer was considered by calculating the bond dissociation energy of the o-hydroxyl group (BDE OH ). 25 We were interested in determining if any of the compounds 3-7 would show greater potential as an antioxidant than gentisic acid (2).…”

N-methyl-2-phenylindole Colorimetric Method as Biomarker for Lipid Peroxidation in Pisum sativum

“…Inhibition of the former has shown to reduce the enzyme from its hydroxide bound ferric (active) form to its water-bound ferrous (inactive) form. Nam et al 13 have suggested a mechanism by which pyrimidine and pyridine type compounds inhibit LOX, by complexation of the iron via a ring nitrogen atom and the carbonyl oxygen of the acetamido group. In this way, inhibition of lipid peroxidation by pyrimi- …”