scholarly journals Studies on 5-Lipoxygenase Inhibitors. II. Discovery, Optical Resolution and Enantioselective Synthesis of FR110302, a Highly Potent Non-redox Type 5-Lipoxygenase Inhibitor.

1998 ◽  
Vol 46 (10) ◽  
pp. 1556-1565 ◽  
Author(s):  
Takumi YATABE ◽  
Hiroshi KAYAKIRI ◽  
Yoshio KAWAI ◽  
Teruo OKU ◽  
Hirokazu TANAKA
Keyword(s):  
Optical Resolution ◽  
Enantioselective Synthesis ◽  
Lipoxygenase Inhibitor ◽  
Lipoxygenase Inhibitors

Process Research Leading to an Enantioselective Synthesis of a 5-Lipoxygenase Inhibitor for Asthma

2003 ◽  
pp. 141-159
Author(s):  
David B. Damon ◽  
Michael Butters ◽  
Robert W. Dugger ◽  
Peter Dunn ◽  
Sally Gut ◽  
...  
Keyword(s):  
Process Research ◽  
Enantioselective Synthesis ◽  
Lipoxygenase Inhibitor

Menthol mediated optical resolution of 10-oxatricyclodecadienones. Application in the enantioselective synthesis of cyclopentenoids

Tetrahedron ◽  
1990 ◽  
Vol 46 (12) ◽  
pp. 4283-4294 ◽  
Author(s):  
Adrie A.M. Houwen-Claassen ◽  
A.J.H. Klunder ◽  
B. Zwanenburg ◽  
Paul T. Beurskens ◽  
F.G. Moers ◽  
...  
Keyword(s):  
Optical Resolution ◽  
Enantioselective Synthesis

L-656,224 (7-chloro-2-[(4-methoxyphenyl)methyl]-3-methyl-5-propyl-4-benzofuranol): a novel, selective, orally active 5-lipoxygenase inhibitor

1987 ◽  
Vol 65 (12) ◽  
pp. 2441-2448 ◽  
Author(s):  
P. Belanger ◽  
A. Maycock ◽  
Y. Guindon ◽  
T. Bach ◽  
A. L. Dollob ◽  
...  
Keyword(s):  
Platelet Activating Factor ◽  
Human Leukocyte ◽  
Lipoxygenase Inhibitor ◽  
Lipoxygenase Inhibitors ◽  
Factor Ii ◽  
Mastocytoma Cells ◽  
Oral Activity ◽  
12 Lipoxygenase ◽  
Rat Paw ◽  
Orally Active

L-656,224 (7-chloro-2-[(4-methoxyphenyl)methyl]-3-methyl-5-propyl-4-benzofuranol) was a potent inhibitor of leukotriene biosynthesis in intact rat and human leukocytes and CXBG mastocytoma cells (IC50 values, 18–240 nM) and of crude human leukocyte and highly purified porcine leukocyte 5-lipoxygenase (IC50 value, 4 × 10–7 M). The selectivity of L-656,224 for 5-lipoxygenase was shown through the relative lack of activity of the compound on 12-lipoxygenase, 15-lipoxygenase, cyclooxygenase, catalase, and myeloperoxidase. The compound showed (i) oral activity against hyperalgesia induced in the rat paw by injection of yeast or platelet-activating factor, (ii) dyspnea in sensitized inbred rats induced by an aerosol of antigen, and (iii) bronchoconstriction induced by an aerosol of Ascaris in squirrel monkeys, suggesting a role for 5-lipoxygenase inhibitors in the treatment of asthma and peripheral pain.

scholarly journals α-Conotoxins Enhance both the In Vivo Suppression of Ehrlich carcinoma Growth and In Vitro Reduction in Cell Viability Elicited by Cyclooxygenase and Lipoxygenase Inhibitors

Marine Drugs ◽  
2020 ◽  
Vol 18 (4) ◽  
pp. 193
Author(s):  
Alexey V. Osipov ◽  
Tatiana I. Terpinskaya ◽  
Tatsiana Yanchanka ◽  
Tatjana Balashevich ◽  
Maxim N. Zhmak ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Antitumor Effect ◽  
Nordihydroguaiaretic Acid ◽  
Ehrlich Carcinoma ◽  
Arachidonic Acid Cascade ◽  
Lipoxygenase Inhibitor ◽  
Lipoxygenase Inhibitors ◽  
Combined Application

Several biochemical mechanisms, including the arachidonic acid cascade and activation of nicotinic acetylcholine receptors (nAChRs), are involved in increased tumor survival. Combined application of inhibitors acting on these two pathways may result in a more pronounced antitumor effect. Here, we show that baicalein (selective 12-lipoxygenase inhibitor), nordihydroguaiaretic acid (non-selective lipoxygenase inhibitor), and indomethacin (non-selective cyclooxygenase inhibitor) are cytotoxic to Ehrlich carcinoma cells in vitro. Marine snail α-conotoxins PnIA, RgIA and ArIB11L16D, blockers of α3β2/α6β2, α9α10 and α7 nAChR subtypes, respectively, as well as α-cobratoxin, a blocker of α7 and muscle subtype nAChRs, exhibit low cytotoxicity, but enhance the antitumor effect of baicalein 1.4-fold after 24 h and that of nordihydroguaiaretic acid 1.8–3.9-fold after 48 h of cell cultivation. α-Conotoxin MII, a blocker of α6-containing and α3β2 nAChR subtypes, increases the cytotoxic effect of indomethacin 1.9-fold after 48 h of cultivation. In vivo, baicalein, α-conotoxins MII and PnIA inhibit Ehrlich carcinoma growth and increase mouse survival; these effects are greatly enhanced by the combined application of α-conotoxin MII with indomethacin or conotoxin PnIA with baicalein. Thus, we show, for the first time, antitumor synergism of α-conotoxins and arachidonic acid cascade inhibitors.

Studies on the roles of phospholipase A2 and eicosanoids in the regulation of corticotrophin secretion by rat pituitary cells in vitro

1991 ◽  
Vol 130 (1) ◽  
pp. 21-32 ◽  
Author(s):  
A. M. Cowell ◽  
R. J. Flower ◽  
J. C. Buckingham
Keyword(s):  
Arachidonic Acid ◽  
Platelet Activating Factor ◽  
Nordihydroguaiaretic Acid ◽  
Cyclooxygenase Inhibitors ◽  
Pituitary Cells ◽  
Lipoxygenase Inhibitor ◽  
Acth Secretion ◽  
Lipoxygenase Inhibitors ◽  
Prostaglandin F

ABSTRACT Dispersed anterior pituitary cells were used to investigate the possible roles of phospholipid metabolites released by phospholipase A2 (PLA2) in the control of immunoreactive ACTH (ir-ACTH) secretion in vitro. PLA2 (15 600–62 500 U/1), the PLA2 activator melittin (0·5–20 mg/l) and arachidonic acid (1 mmol/l) all produced increases in ir-ACTH release from the cells, whilst platelet-activating factor (PAF), prostaglandin F2α (PGF2α), the prostacyclin analogues iloprost and BW245C, the thromboxane A2 (TXA2) analogue U46619, and the leukotrienes LTB4 and LTC4 were ineffective in this respect. PGF2α (100 nmol/l and 1 μmol/l), iloprost (1 μmol/l) and BW245C (100 nmol/l and 1 μmol/l) depressed corticotrophin-releasing factor-41-induced ir-ACTH secretion, while the PAF antagonist BN52021 (10 and 100 μmol/l) and LTC4 (100 nmol/l and 1 μmol/l) had no discernable effects. The secretory responses of the cells to hypothalamic extracts (0·2 hypothalami/ml) and arachidonic acid (1 mmol/l) were generally unaffected by the cyclooxygenase inhibitors ibuprofen (10 and 100 μmol/l) and indomethacin (10 μmol/l), the TXA2 synthetase inhibitor imidazole (10 μmol/l–1 mmol/l), the lipoxygenase inhibitor nordihydroguaiaretic acid (10 and 100 μmol/l) and the dual cyclo-oxygenase/lipoxygenase inhibitors phenidone (1–100 μmol/l) and BW755C (10 and 100 μmol/l). They were, however, inhibited by the dual cyclo-oxygenase/lipoxygenase inhibitor eicosatetraynoic acid (10 and 100 μmol/l), which also blocks epoxygenase and PLA2 activity and by the cytochrome P450 inhibitor SKF-525A (1 mmol/l). The results suggest that the stimulatory effects of PLA2 and arachidonic acid on ir-ACTH secretion are not effected by products generated by the cyclo-oxygenase or lipoxygenase pathways but may be mediated by metabolites generated by the cytochrome P450 pathway. Journal of Endocrinology (1991) 130, 21–32

Lipoxygenase inhibitors block PDGF-induced mitogenesis: a MAPK-independent mechanism that blocks fos and egr

1995 ◽  
Vol 268 (3) ◽  
pp. C604-C610 ◽  
Author(s):  
D. W. Beno ◽  
J. Mullen ◽  
B. H. Davis
Keyword(s):  
Mechanism Of Action ◽  
Nordihydroguaiaretic Acid ◽  
Receptor Activation ◽  
Mitogen Activated Protein Kinase ◽  
Pdgf Receptor ◽  
Lipoxygenase Inhibitor ◽  
Ito Cells ◽  
Lipoxygenase Inhibitors ◽  
Nuclear Signaling ◽  
Lipoxygenase Inhibition

Hepatic Ito cells proliferate during liver injury and fibrogenesis. Platelet-derived growth factor (PDGF)-induced [3H]thymidine incorporation was studied as Ito cells express the PDGF receptor after injury and activation. Pretreatment with either the nonspecific lipoxygenase inhibitor (nordihydroguaiaretic acid) or specific inhibitors of 5-lipoxygenase (SC-41661 and ICI-230487) inhibited PDGF-induced mitogenesis. Ito cells predominantly produce the leukotriene (LT) C4 >> LTB4. The PDGF-induced signal transduction cascade was studied to determine the potential mechanism of action of the lipoxygenase inhibitors. It was found that PDGF receptor abundance and receptor activation were not altered by lipoxygenase inhibition, suggesting that a postreceptor mechanism was involved. The two-key cytoplasmic serine-threonine kinases Raf and MAPK (mitogen-activated protein kinase), which are induced by PDGF and transmit the signal to the nucleus, were also not altered. Because Raf and MAPK can independently induce nuclear signaling, this suggests that the mechanism of action lies parallel or distal to these secondary messengers. Lipoxygenase inhibition did result in the suppression of PDGF-induced fos and egr expression. Collectively, this work suggests that lipoxygenase inhibition leads to the suppression of mitogenesis in part by disrupting the nuclear signaling that is required for protooncogene transcription at a step distal or parallel to MAPK activation.

ChemInform Abstract: Menthol Mediated Optical Resolution of 10-Oxatricyclodecadienones. Application in the Enantioselective Synthesis of Cyclopentenoids.

ChemInform ◽  
1990 ◽  
Vol 21 (42) ◽  
Author(s):  
A. A. M. HOUWEN-CLAASSEN ◽  
A. J. H. KLUNDER ◽  
B. ZWANENBURG ◽  
P. T. BEURSKENS ◽  
F. G. MOERS ◽  
...  
Keyword(s):  
Optical Resolution ◽  
Enantioselective Synthesis

scholarly journals New Hydroxycinnamic Acid Esters as Novel 5-Lipoxygenase Inhibitors That Affect Leukotriene Biosynthesis

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Luc H. Boudreau ◽  
Grégoire Lassalle-Claux ◽  
Marc Cormier ◽  
Sébastien Blanchard ◽  
Marco S. Doucet ◽  
...  
Keyword(s):  
Caffeic Acid ◽  
Inhibitory Activity ◽  
Inflammatory Diseases ◽  
Caffeic Acid Phenethyl Ester ◽  
Lipoxygenase Inhibitor ◽  
Lipoxygenase Inhibitors ◽  
Naturally Occurring ◽  
Key Enzyme ◽  
Hydroxycinnamic Acid Esters ◽  
Acid Esters

Leukotrienes are inflammatory mediators that actively participate in the inflammatory response and host defense against pathogens. However, leukotrienes also participate in chronic inflammatory diseases. 5-lipoxygenase is a key enzyme in the biosynthesis of leukotrienes and is thus a validated therapeutic target. As of today, zileuton remains the only clinically approved 5-lipoxygenase inhibitor; however, its use has been limited due to severe side effects in some patients. Hence, the search for a better 5-lipoxygenase inhibitor continues. In this study, we investigated structural analogues of caffeic acid phenethyl ester, a naturally-occurring 5-lipoxygenase inhibitor, in an attempt to enhance the inhibitory activity against 5-lipoxygenase and determine structure-activity relationships. These compounds were investigated for their ability to attenuate the biosynthesis of leukotrienes. Compounds 13 and 19, phenpropyl and diphenylethyl esters, exhibited significantly enhanced inhibitory activity when compared to the reference molecules caffeic acid phenethyl ester and zileuton.

Zileuton: The First 5-Lipoxygenase Inhibitor for the Treatment of Asthma

1996 ◽  
Vol 30 (7-8) ◽  
pp. 858-864 ◽  
Author(s):  
Sally E Wenzel ◽  
Alan K Kamada
Keyword(s):  
English Language ◽  
Science Studies ◽  
Ex Vivo ◽  
Data Extraction ◽  
Lipoxygenase Inhibitor ◽  
Lipoxygenase Inhibitors ◽  
Medline Search ◽  
Elevated Liver Enzymes ◽  
Considerable Benefit

OBJECTIVE: To introduce and review zileuton, an orally active 5-lipoxygenase inhibitor that represents the first of a new class of medications to be used in the treatment of asthma. DATA SOURCES: A MEDLINE search (from 1966 to December 1995) was performed to identify pertinent English-language literature. STUDY SELECTION: Basic science studies on the pharmacokinetics of zileuton, its pathophysiologic effects on asthma, and clinical efficacy trials were reviewed. DATA EXTRACTION: Clinical trials were emphasized. Studies from ex vivo or animal models of pharmacologic and pharmacodynamic effects were considered for review where no in vivo human data were available. DATA SYNTHESIS: Zileuton has shown the ability to attenuate induced bronchospasm, produce some degree of bronchodilation, and provide antiinflammatory or steroid-sparing effects with both single doses (800 mg) and chronic treatment (400 and 600 mg qid). Zileuton has been studied in patients requiring daily inhaled beta-adrenergic agonist treatment; however, data from pediatric populations and comparisons with other asthma medications are limited at this time. Adverse effects include dyspepsia and elevated liver enzymes (incidence ∼3%). One case of jaundice has been reported among the more than 5000 patients treated with zileuton. There is also some concern for drug interactions with hepatically cleared medications, such as theophylline. CONCLUSIONS: Zileuton represents the first drug of a new treatment category for asthma, the 5-lipoxygenase inhibitors. Some people with asthma may receive considerable benefit, but as it is an entirely new drug entity, zileuton's final place in the hierarchy of asthma medications remains to be determined.

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