Arylmethyl Phenyl Ethers

Coutts, Stephen M.; Khandwala, Atul; Inwegen, Richard Van; Chakraborty, Utpal; Musser, John H.; Bruens, John; Jariwala, N.; Dally-Meade, Vernetta; Ingram, Richard; Pruss, T. P.; Jones, Howard; Neiss, E. S.; Weinryb, Ira

doi:10.1007/978-1-4684-4946-4_60

Cited by 20 publications

(5 citation statements)

References 10 publications

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“…3) and longer (up to 24 h, Fig. 4) incubations of iron-binding HP-4-ones with sbLPO show similar degrees of inhibition to cellular 5-LPO, contrasting with known translocation inhibitors, which are considerably less active in cell-free compared with the cellular systems (37,40). Translocation-type inhibition is unlikely to be a major mechanism with iron chelators but could account for some of the effects of Ome-25.…”

Section: Discussionmentioning

confidence: 71%

The Environment of the Lipoxygenase Iron Binding Site Explored with Novel Hydroxypyridinone Iron Chelators

Abeysinghe

Roberts

Cooper

et al. 1996

Journal of Biological Chemistry

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The mechanisms of lipoxygenase inhibition by iron chelators have been investigated in human neutrophils and in isolated soybean lipoxygenase. Their Fe(III)-containing active sites have been targeted by synthesizing novel bidentate chelators from the hydroxypyridinone family sufficiently small to gain access through the hydrophobic channels of lipoxygenase. In stimulated human neutrophils, release of [3H]arachidonate-labeled eicosanoids is dependent on the lipid solubility of hydroxypyridinones, but larger hexadentate chelators have no effect on this or on total cellular leukotriene B4 production. Lipophilic hydroxypyridinones inhibit 5-lipoxygenase at equivalent concentrations to the established inhibitor, piriprost, and show additional but minor anti-phospholipase A2 activity. Soybean 15-lipoxygenase inhibition is also dependent on the lipid solubility and coordination structure of chelators. Inhibition is associated with the formation of chelate-iron complexes, which are removed by dialysis without restoration of enzyme activity. Only after adding back iron is activity restored. Electron paramagnetic resonance studies show the removal of the iron center signal (g = 6) is concomitant with formation of Fe(III)-chelator complexes, identical in spectral shape and g value to 3:1 hydroxypyridinone Fe(III) complexes. Removal of iron is not the only mechanism by which hydroxypyridinones can inhibit lipoxygenase in intact cells, however, as a lipophilic non-iron-binding hydroxypyridinone, which shows no inhibition of the soybean lipoxygenase activity, partially inhibits 5-lipoxygenase in intact neutrophils without inhibiting neutrophil phospholipase A2.

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Section: Discussionmentioning

confidence: 71%

The Environment of the Lipoxygenase Iron Binding Site Explored with Novel Hydroxypyridinone Iron Chelators

Abeysinghe

Roberts

Cooper

et al. 1996

Journal of Biological Chemistry

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“…The cyclo-oxygenase inhibitors, indomethacin and flurbiprofen, inhibited arachidonic acid-induced plasma extravasation but less effectively than the 5-lipoxygenase inhibitors, quercetin and NDGA. AA861 and REV5901 which have been shown to be selective 5-lipoxygenase inhibitors (Ashida et al, 1982;Coutts et al, 1985) were also inhibitory. Although REV5901 caused a concentration-dependent inhibition of arachidonic acid-induced plasma extravasation it had no statistically a) 100- Drug concentration (,ug per site) Figure 5 The effect of mixed cyclo-oxygenase and lipoxygenase inhibitors on arachidonic acid-induced inflammation in rabbit skin: phenidone (0); BW755C (0).…”

Section: Pharmacological Modulationmentioning

confidence: 98%

The inflammatory response of rabbit skin to topical arachidonic acid and its pharmacological modulation

Aked

Foster

Howarth

et al. 1986

British J Pharmacology

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The inflammatory reaction induced by the intradermal injection of arachidonic acid into the rabbit dermis has been investigated. Plasma extravasation was measured by the leakage of 125I‐albumin into the tissues and polymorphonuclear leukocyte (PMNL) accumulation was assessed histologically. Arachidonic, 5,8,11,14,17‐eicosapentaenoic and 8,11,14‐eicosatrienoic acids, but not oleic, linoleic or linolenic acids, caused a concentration‐related plasma extravasation following their intra‐dermal injection. The plasma extravasation induced by arachidonic acid was dependent on PMNLs. PMNL infiltration and plasma extravasation into arachidonic acid‐injected skin sites was inhibited by the mixed cyclo‐oxygenase‐lipoxygenase inhibitor, BW755C. Arachidonic acid‐induced plasma extravasation was inhibited by cyclo‐oxygenase and 5‐lipoxygenase inhibitors but not by the Paf antagonist, kadsurenone. The inflammation induced by arachidonic acid in the rabbit dermis may be a useful model for evaluating 5‐lipoxygenase inhibitors which could be potentially useful anti‐inflammatory agents for the treatment of psoriasis and other inflammatory diseases.

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“…The positional isomers 96 and 45 were prepared and found to inhibit 5-LO LTD 4 receptor [82]. Compounds 97 and 98 were derived from 96 [83]. Compound 99 was prepared by Wyeth-Ayerst by incorporating quinolylmethyloxy pharmacophore to the effective compound 78; it was active, but showed significant mutagenicity [61].…”

Section: Compounds With Dual Activitymentioning

confidence: 99%

5-Lipoxygenase, Leukotrienes Biosynthesis and Potential Antileukotrienic Agents

Jampílek¹,

Doležal²,

Opletalová³

et al. 2006

CMC

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Leukotrienes play an important role in the inflammatory process accompanying allergic diseases of respiratory, gastrointestinal and dermatological systems. Leukotrienes are generated from arachidonic acid as a result of the 5-lipoxygenase action. This paper deals with 5-lipoxygenase action mechanism and the following biosynthesis of all leukotrienes. In this article, potential antileukotrienic agents are classified according to their mechanism of action. The original antileukotrienic compounds of the Research Institute for Pharmacy and Biochemistry in Prague (VUFB), Czech Republic are presented in a separate chapter of the paper.

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Arylmethyl Phenyl Ethers

Cited by 20 publications

References 10 publications

The Environment of the Lipoxygenase Iron Binding Site Explored with Novel Hydroxypyridinone Iron Chelators

The Environment of the Lipoxygenase Iron Binding Site Explored with Novel Hydroxypyridinone Iron Chelators

The inflammatory response of rabbit skin to topical arachidonic acid and its pharmacological modulation

5-Lipoxygenase, Leukotrienes Biosynthesis and Potential Antileukotrienic Agents

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