bwa-4c and zileuton

The potential involvement of lipoxygenase metabolites in the tumour growth stimulatory activity of arachidonic and linoleic acid has been studied using the 5-lipoxygenase inhibitors, BWA4C, BWB70C and Zileuton. In vitro the former two agents were relatively potent inhibitors of growth of murine adenocarcinomas (MACs) with IC50 values < 10 microM, whereas Zileuton was less effective. In vivo studies showed BWA4C to be an effective inhibitor of the growth of both the MAC26 and MAC16 tumours at dose levels between 5 and 25 mg kg-1 (b.d.). The growth rate of the MAC26 tumour was also decreased by BWB70C at 25 mg kg-1, whereas lower doses were either ineffective or stimulated tumour growth. This differential effect of the 5-lipoxygenases inhibitors on tumour growth may arise from effects on the 12- and 15-lipoxygenase pathways. To quantify the effect cells were labelled with [3H]arachidonic acid and the biosynthesis of 5-, 12- and 15-hydroxyeicosatetraenoic acid (HETE) was analysed by high-performance liquid chromatography. All three agents caused a decrease in 5-HETE production, although the effect was less pronounced with Zileuton. In MAC26 cells both BWA4C and BWB70C caused a decrease in 12-HETE formation whereas Zileuton had no effect on the other lipoxygenase pathways. The inhibitory effect of these agents on cell growth may result from an imbalance of metabolism of arachidonic acid between the 5-, 12- and 15-lipoxygenase pathways.

Topics: Adenocarcinoma; Administration, Oral; Analysis of Variance; Animals; Benzeneacetamides; Cell Division; Colonic Neoplasms; Hydroxamic Acids; Hydroxyurea; Lipoxygenase Inhibitors; Male; Mice; Neoplasm Transplantation; Treatment Outcome; Tumor Cells, Cultured

Methoxyalkyl thiazoles have been identified as a novel series of selective 5-lipoxygenase inhibitors with anti-inflammatory properties (Bird et al., J Med Chem 34: 2176-2186, 1991). Based on their structure, it was proposed that the potency of these compounds is not due to redox or iron-chelating properties. In the studies reported here, it was found that the model compounds 1-[3-(naphth-2-ylmethoxy)phenyl]-1-(thiazol-2-yl)propy l methyl ether (ICI 211965) and 3-[1-(4-chlorobenzyl)-4-methyl-6-(5- phenylpyridin-2-ylmethoxy)-4,5-dihydro-1H-thiopyrano[2 ,3,4-c,d]indol-2- yl]-2,2-dimethylpropanoic acid (L-689,065) (1) are inactive as reducing substrates in the 5-lipoxygenase-catalyzed decomposition of lipid hydroperoxides, (2) inhibit the 5-lipoxygenase-catalyzed reaction of reducing agents with lipid hydroperoxides, and (3) strongly inhibit the turnover-dependent inactivation of 5-lipoxygenase. These three observations with ICI 211965 and L-689,065 are in contrast to the behavior of other potent 5-lipoxygenase inhibitors from other structural classes, such as L-670,630, BW A4C, and zileuton, which all function as reducing substrates for 5-lipoxygenase. The data indicate that methoxyalkyl thiazoles and thiopyranoindoles are reversible dead-end inhibitors of 5-lipoxygenase and that the effects of inhibitors on the pseudoperoxidase activity and rate of enzyme inactivation provide simple tests to distinguish between redox and non-redox inhibitors of 5-lipoxygenase.

Topics: Arachidonate 5-Lipoxygenase; Benzeneacetamides; Benzofurans; Enzyme Inhibitors; Humans; Hydroxamic Acids; Hydroxyurea; Indoles; Leukotrienes; Lipid Peroxides; Lipoxygenase Inhibitors; Naphthalenes; Oxidation-Reduction; Thiazoles

One proposed mechanism of the inactivation of lipoxygenase by inhibitors is the reduction of the catalytically active ferric form of the enzyme to its ferrous form. Recent studies have shown that compounds containing the hydroxamate moiety are potent inhibitors of lipoxygenase. The hydroxamate portion of the inhibitor is thought to bind to iron at the catalytic site of the enzyme. We now report evidence that the NOH of the hydroxamate group of N-(4-chlorophenyl)-N-hydroxy-N'-(3-chlorophenyl)urea, N-[(E)-3-(3-phenoxyphenyl)prop-2-enyl]acetohydroxamic acid (BW A4C), and N-(1-benzo(b)thien-2-ylethyl)-N-hydroxyurea (Zileuton) is oxidized by lipoxygenase to form their corresponding nitroxides, which are directly detected by electron paramagnetic resonance spectroscopy. It is consistently found that the selected NOH-containing compounds, e.g. alkylhydroxylamines or N-hydroxyureas, are also oxidized by lipoxygenase to form their corresponding nitroxides.

Topics: Benzeneacetamides; Electron Spin Resonance Spectroscopy; Free Radicals; Glycine max; Hydroxamic Acids; Hydroxylamines; Hydroxyurea; Lipoxygenase Inhibitors; Molecular Structure; Nitrogen Oxides; Oxidation-Reduction; Structure-Activity Relationship