Substituted arylmethyl phenyl ethers. 1. A novel series of 5-lipoxygenase inhibitors and leukotriene antagonists

Musser, John H.; Chakraborty, Utpal; Sciortino, Stanley; Gordon, Robert J.; Khandwala, Atul; Neiss, E. S.; Pruss, T. P.; Inwegen, Richard Van; Weinryb, Ira; Coutts, Stephen M.

doi:10.1021/jm00384a017

Cited by 51 publications

(30 citation statements)

References 1 publication

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“…We therefore concluded that LTs are involved in the Ca 2ϩ -dependent acidification in RAW 264.7 macrophages. In this context, the inhibitory effect of REV 5901, a potent inhibitor of 5-lipoxygenase (Musser et al, 1987) as well as a competitive antagonist of peptide LTs , on UTPinduced acidification (Table 1) also supports this notion. These findings provide a novel downstream mechanism for AA-induced intracellular acidification.…”

mentioning

confidence: 60%

“…AA-induced intracellular acidosis also was abolished by pretreatment with MK-886 (10 M) plus baicalein (10 M) (three experiments, data not shown). REV 5901, a 5-lipoxygenase inhibitor (Musser et al, 1987) as well as a competitive antagonist of peptide LTs (Musser et al, 1987), also markedly attenuated the UTP response (Table 1). All the drugs tested had no cytotoxic effects on RAW 264.7 cells as determined by MTT assays (data not shown).…”

Section: Utp-induced Extracellular Camentioning

confidence: 96%

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Lipoxygenase Metabolites as Mediators of UTP-Induced Intracellular Acidification in Mouse RAW 264.7 Macrophages

Lin

Chang

1998

Mol Pharmacol

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In previous studies, we have shown that mouse RAW 264.7 macrophages possess pyrimidinoceptors, coupled to a phosphoinositide-specific phospholipase C, with a higher specificity for UTP than for ATP. In the current study, we explored the mechanism involved in the UTP-induced intracellular acidification seen in this cell line. UTP (30 M) caused a reversible pH i decrease of 0.16 Ϯ 0.01 unit; this effect was not influenced by the removal of extracellular Cl Ϫ or Na ϩ ions or by pretreatment with 5-(N-ethyl-N-isopropyl)-amiloride (10 M), 5-nitro-2-(3-phenylpropylamino)benzoic acid (100 M), staurosporine (1 M), or Ro 31-8220 (1 M) but was completely abolished by the removal of extracellular Ca 2ϩ . UTP (30 M), thapsigargin (1 M), and ionomycin (1 M) each induced a similar extent of external Ca 2ϩ -dependent acidification with a similar time-dependency, but the effects were nonadditive. To further investigate the Ca 2ϩ -dependent mechanism, we studied the involvement of arachidonic acid (AA) and eicosanoid metabolites. The addition of AA (10 M) but not arachidic acid (100 M) produced a reduction in pH i . UTP, thapsigargin, and ionomycin induced Ca 2ϩ -dependent AA release. Furthermore, 4-bromo-phenacyl bromide [30 M, a phospholipase A 2 (PLA 2 ) inhibitor], nordihydroguaiaretic acid (50 M, a lipoxygenase inhibitor), and MK-886 (10 M, a 5-lipoxygenase-activating protein inhibitor) abolished the UTP-or ionomycin-induced responses, whereas indomethacin (30 M, a cyclooxygenase inhibitor) and baicalein (10 M, a selective 12-lipoxygenase inhibitor) had no effect. MAFP (a cPLA 2 inhibitor) and REV 5901 (a 5-lipoxygenase inhibitor as well as a competitive antagonist of peptide leukotrienes), but not RHC 80267 (a diacylglycerol lipase inhibitor), also inhibited the UTP-induced response. In contrast, the pH i response to AA was unaffected by the presence of 4-bromophenacyl bromide or the removal of extracellular Ca 2ϩ ions but abolished by addition of NDGA. Exogenous 5-hydroperoxyeicosatetraenoic acid (2 M) also produced marked acidification, and UTP and ionomycin both induced peptide leukotriene formation. In conclusion, this is the first report indicating that lipoxygenase metabolites act as mediators of the Ca 2ϩ -dependent acidification seen in macrophages in response to UTP or ionomycin via activation of cPLA 2 and AA release.

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confidence: 60%

Section: Utp-induced Extracellular Camentioning

confidence: 96%

Lipoxygenase Metabolites as Mediators of UTP-Induced Intracellular Acidification in Mouse RAW 264.7 Macrophages

Lin

Chang

1998

Mol Pharmacol

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“…We also studied the role of the LOX pathway on 3T6 fibroblast proliferation with LT receptor antagonists. We used U-75302, REV-5901, and LY-171883 as LTB 4 , LTD 4 , and CysLT receptor antagonists, respectively (28)(29)(30). All antagonists induced a low growth and […”

Section: Effect Of Lox Inhibitors and Lt Receptor Antagonists On The mentioning

confidence: 99%

Hydroxyeicosatetraenoic acids released through the cytochrome P-450 pathway regulate 3T6 fibroblast growth

Nieves

Moreno

2006

Journal of Lipid Research

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Eicosanoids participate in the regulation of cellular proliferation. Thus, we observed that prostaglandin E 2 interaction with membrane receptors is involved in the control of 3T6 fibroblast growth induced by serum. However, our results suggested that another arachidonic acid pathway might be implicated in these events. Our results show that 3T6 fibroblasts synthesized hydroxyeicosatetraenoic acids (HETEs) such as 12-HETE through the cytochrome P-450 (CYP450) pathway. However, 3T6 fibroblasts did not produce leukotriene B 4 (LTB 4 ), and lipoxygenase inhibitors and LT antagonists failed to inhibit 3T6 fibroblast growth induced by FBS. In contrast, we observed that CYP450 inhibitors such as SKF-525A, 17-octadecynoic acid, 1-aminobenzotriazole, and 6-(2-propargyloxyphenyl)hexanoic acid reduced 12(S)-HETE levels, 3T6 fibroblast growth, and DNA synthesis induced by FBS. The impairment of DNA synthesis and 3T6 fibroblast growth induced by SKF-525A were reversed by exogenous addition of HETEs. Moreover, we report that 5-HETE, 12(S)-HETE, and 15(S)-HETE are mitogenic on 3T6 fibroblast in the absence of another growth factor, and this effect was dependent on the activation of the phosphatidylinositol-3-kinase pathway. In conclusion, our results show that HETEs, probably produced by CYP450, are involved in the control of 3T6 fibroblast growth.-Nieves, D., and J. J. Moreno. Hydroxyeicosatetraenoic acids released through the cytochrome P-450 pathway regulate 3T6 fibroblast growth. Free arachidonic acid (AA) can be oxidized by three major metabolic pathways: the cyclooxygenases (COXs), which produce prostaglandins (PGs) and thromboxanes; the lipoxygenases (LOXs), which form leukotrienes (LTs), hydroxyeicosatetraenoic acids (HETEs), and lipoxins; and the cytochrome P-450 monooxygenases (CYP450s) (1). The CYP450 proteins metabolized AA by one or more of the following reactions: bis-allylic oxidation (LOX-like reaction) to generate 5-, 8-, 9-, 11-, 12-, and 15-HETEs; v/v-1 hydroxylation gives 16-, 17-, 18-, 19-, and 20-HETEs; or olefin epoxidation, producing 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs). Finally, the cytosolic epoxide hydrolases catalyze a rapid enzymatic hydration of the EETs to dihydroxyeicosatetraenoic acids (2).Eicosanoids have numerous physiological effects (3), including cell proliferation and differentiation. Recent studies in our laboratory have suggested that the COX pathway is involved in serum-induced 3T6 fibroblast proliferation. On the one hand, we have demonstrated that COX-2 inhibition reduces 3T6 fibroblast proliferation in a concentration-dependent manner, producing an z50% maximum effect (4). On the other hand, we have shown that EP 1 and EP 4 receptors of PGE 2 antagonists reduced 3T6 fibroblast growth in a concentration-dependent manner, but to almost complete inhibition (5). Furthermore, we have reported that phospholipase A 2 (PLA 2 ) inhibitors reduced serum-induced 3T6 fibroblast growth and [ 3 H]thymidine incorporation almost completely (6). These results sugg...

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“…[42] Diethyl (2-Cyanobenzyl)phosphonate (20), [43] Diethyl (3-Cyanobenzyl)phosphonate (21), [44] and Diethyl (4-Cyanobenzyl)phosphonate (23) [45] : These compounds were prepared from the commercially available chloromethyl benzonitriles and triethyl phosphite according to the procedures given above.…”

Section: Diethyl [4-(hexyloxy)benzyl]phosphonate (19)mentioning

confidence: 99%

Synthesis, Structure and Solvatochromism of the Emission of Cyano-Substituted Oligo(phenylenevinylene)s

2001

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Strongly luminescent and highly soluble oligo(phenylenevinylene)s with five benzene rings and cyano groups in different positions of the terminal styrene units were prepared by means of Horner and Knoevenagel reactions. The substitution pattern − cyanide moieties on the vinyl or on the aromatic regions, together with the effect of auxochromic groups − has distinct influences on the electronic spectra, particularly on the fluorescence. Polar solvents induce red shifts and strongly reduce the fluorescence intensity of the vinyl‐substituted oligomers. Cyano substitution increases the electron affinity of the oligomers; this effect is more pronounced for molecules with vinyl cyanides and can be altered by the presence of additional electron‐donating or electron‐withdrawing groups. The molecular structures of one oligomer bearing cyano groups on the vinylene segments and one with benzonitrile units have been resolved.

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Substituted arylmethyl phenyl ethers. 1. A novel series of 5-lipoxygenase inhibitors and leukotriene antagonists

Cited by 51 publications

References 1 publication

Lipoxygenase Metabolites as Mediators of UTP-Induced Intracellular Acidification in Mouse RAW 264.7 Macrophages

Lipoxygenase Metabolites as Mediators of UTP-Induced Intracellular Acidification in Mouse RAW 264.7 Macrophages

Hydroxyeicosatetraenoic acids released through the cytochrome P-450 pathway regulate 3T6 fibroblast growth

Synthesis, Structure and Solvatochromism of the Emission of Cyano-Substituted Oligo(phenylenevinylene)s

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