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5 lipoxygenase inhibitors

Daniel Pettersen, Johan Broddefalk, Hans Emtenäs, Martin A Hayes, Malin Lemurell, Marianne Swanson, Johan Ulander, Carl Whatling, Carl Amilon, Hans Ericsson, Annika Westin Eriksson, Kenneth Granberg, Alleyn T Plowright, Igor Shamovsky, Anita Dells Eacute N, Monika Sundqvist, Mats Någård, Eva-Lotte Lindstedt
5-lipoxygenase activating protein (FLAP) inhibitors attenuate 5-lipoxygenase pathway activity and reduce the production of pro-inflammatory and vasoactive leukotrienes. As such, they are hypothesized to have therapeutic benefit for the treatment of diseases that involve chronic inflammation including coronary artery disease. Herein, we disclose the medicinal chemistry discovery and the early clinical development of the FLAP inhibitor AZD5718 (12). Multiparameter optimization included securing adequate potency in human whole blood, navigation away from Ames mutagenic amine fragments whilst balancing metabolic stability and PK properties allowing for clinically relevant exposures after oral dosing...
March 14, 2019: Journal of Medicinal Chemistry
Lu Liu, Nayiyuan Wu, Ying Wang, Xiaoyun Zhang, Bing Xia, Jie Tang, Jingting Cai, Zitong Zhao, Qianjin Liao, Jing Wang
BACKGROUND: The epithelial-mesenchymal transition (EMT) is crucial for metastasis and positively regulated by calcium-related signaling. The melastatin-related transient receptor potential 7 (TRPM7) regulates a non-selective cation channel and promotes cancer metastasis. However, the mechanisms underlying the action of TRPM7 in ovarian cancer are unclear. METHODS: The expression of TRPM7 and EMT markers (Vimentin, N-cadherin, Twist and E-cadherin) in ovarian cancer samples was detected...
February 28, 2019: Journal of Experimental & Clinical Cancer Research: CR
Stefanie König, Simona Pace, Helmut Pein, Thorsten Heinekamp, Jan Kramer, Erik Romp, Maria Straßburger, Fabiana Troisi, Anna Proschak, Jan Dworschak, Kirstin Scherlach, Antonietta Rossi, Lidia Sautebin, Jesper Z Haeggström, Christian Hertweck, Axel A Brakhage, Jana Gerstmeier, Ewgenij Proschak, Oliver Werz
The epidithiodioxopiperazine gliotoxin is a virulence factor of Aspergillus fumigatus, the most important airborne fungal pathogen of humans. Gliotoxin suppresses innate immunity in invasive aspergillosis, particularly by compromising neutrophils, but the underlying molecular mechanisms remain elusive. Neutrophils are the first responders among innate immune cells recruited to sites of infection by the chemoattractant leukotriene (LT)B4 that is biosynthesized by 5-lipoxygenase and LTA4 hydrolase (LTA4 H). Here, we identified gliotoxin as inhibitor of LTA4 H that selectively abrogates LTB4 formation in human leukocytes and in distinct animal models...
January 17, 2019: Cell Chemical Biology
Yun Huang, Shaoling Huang, Yue Wu, Minlan Peng, Xinge Zhang, Jing Wang, Jianan Hu
Metabolic activation of indirect-acting carcinogens in the target organ is an effective mechanism of carcinogenesis. Lipoxygenase (LOX) can co-oxidize the bladder carcinogen benzidine (BZ). However, it is not entirely clear whether BZ is activated and which enzyme is involved in its activation in bladder epithelial cells. Our results showed that BZ induced 5-LOX protein expression but had no significant influence on the expression of 15-LOX-2, CYP1B1, and CYP2E1 in SV-40 immortalized human uroepithelial SV-HUC-1 cells...
February 10, 2019: International Journal of Toxicology
Markus Werner, Paul M Jordan, Erik Romp, Anna Czapka, Zhigang Rao, Christian Kretzer, Andreas Koeberle, Ulrike Garscha, Simona Pace, Hans-Erik Claesson, Charles N Serhan, Oliver Werz, Jana Gerstmeier
Nonsteroidal anti-inflammatory drugs interfere with the metabolism of arachidonic acid to proinflammatory prostaglandins and leukotrienes by targeting cyclooxygenases (COXs), 5-lipoxygenase (LOX), or the 5-LOX-activating protein (FLAP). These and related enzymes act in conjunction with marked crosstalk within a complex lipid mediator (LM) network where also specialized proresolving LMs (SPMs) are formed. Here, we present how prominent LM pathways can be differentially modulated in human proinflammatory M1 and proresolving M2 macrophage phenotypes that, upon exposure to Escherichia coli, produce either abundant prostaglandins and leukotrienes (M1) or SPMs (M2)...
February 8, 2019: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Md Monirujjaman, Harold M Aukema
BACKGROUND: Increased levels of cyclooxygenase (COX) derived oxylipins is the earliest and most consistent alteration in the renal oxylipin profile in diverse models of cystic kidney diseases. Therefore, we examined whether a COX2 inhibitor would reduce disease progression in the Pkd2WS25/- mouse model of autosomal dominant polycystic kidney disease (ADPKD). METHODS: Weanling normal and diseased male Pkd2 mice were provided diets that provided 0 or 50 mg celecoxib/kg body weight/day, for 13 weeks...
January 22, 2019: Journal of Nephrology
Biswajit Bose, Debabrata Tripathy, Anupam Chatterjee, Pramod Tandon, Suman Kumaria
ETHNOPHARMACOLOGICAL RELEVANCE: Nardostachys jatamansi (D. Don) DC., 'Spikenard' or 'Jatamansi', a highly valued, aromatic herb from alpine Himalayas has a long history of use as ethnomedicine and dietary supplements in Ayurveda, Unani and Chinese system of medicine since Vedic ages (1000-800 BC). In Ayurveda and traditional system of medicine, the species is used as stimulant, sedative, brain tonic or mind rejuvenator, antidiabetic, cardio tonic, and in the treatment of various neurological disorders such as insomnia, epilepsy, hysteria, anxiety and depression...
August 8, 2018: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Lisa Vieider, Erik Romp, Veronika Temml, Jana Fischer, Christian Kretzer, Martin Schoenthaler, Abdulla Taha, Victor Hernández-Olmos, Sonja Sturm, Daniela Schuster, Oliver Werz, Ulrike Garscha, Barbara Matuszczak
A series of derivatives of the potent dual soluble epoxide hydrolase (sEH)/5-lipoxygenase-activating protein (FLAP) inhibitor diflapolin was designed, synthesized, and characterized by 1 H NMR, 13 C NMR, and elemental analysis. These novel compounds were biologically evaluated for their inhibitory activity against sEH and FLAP. Molecular modeling tools were applied to analyze structure-activity relationships (SAR) on both targets. Results show that even small modifications on the lead compound diflapolin markedly influence the inhibitory potential, especially on FLAP, suggesting very narrow SAR...
January 10, 2019: ACS Medicinal Chemistry Letters
John R Montford, Colin Bauer, Evgenia Dobrinskikh, Katharina Hopp, Moshe Levi, Mary Cm Weiser-Evans, Raphael A Nemenoff, Seth B Furgeson
In inflammatory diseases, the 5-lipoxygenase (5-LO) pathway contributes to epithelial damage and fibrosis by catalyzing the production of leukotrienes. Antagonists of the 5-LO pathway are currently approved for use in patients and are well tolerated. We found that expression of 5-LO is strongly induced in three models of chronic kidney disease, unilateral ureteral obstruction (UUO), folate nephropathy, and an orthologous mouse model of polycystic kidney disease. Immunohistochemistry showed that macrophages are the dominant source of 5-LO...
January 16, 2019: American Journal of Physiology. Renal Physiology
Subramani Muthuraman, Shweta Sinha, C S Vasavi, Kamran Manzoor Waidha, Biswarup Basu, Punnagai Munussami, M M Balamurali, Mukesh Doble, Rajendran Saravana Kumar
5-Lipoxygenase (5-LOX) is a key enzyme involved in the biosynthesis of pro-inflammatory leukotrienes, leading to asthma. Developing potent 5-LOX inhibitors especially, natural product based ones, are highly attractive. Coumaperine, a natural product found in white pepper and its derivatives were herein developed as 5-LOX inhibitors. We have synthesized twenty four derivatives, characterized and evaluated their 5-LOX inhibition potential. Coumaperine derivatives substituted with multiple hydroxy and multiple methoxy groups exhibited best 5-LOX inhibition...
January 3, 2019: Bioorganic & Medicinal Chemistry
Thalia Liargkova, Nikolaos Eleftheriadis, Frank Dekker, Efstathia Voulgari, Constantinos Avgoustakis, Marina Sagnou, Barbara Mavroidi, Maria Pelecanou, Dimitra Hadjipavlou-Litina
Chalcones represent a class of small drug/druglike molecules with different and multitarget biological activities. Small multi-target drugs have attracted considerable interest in the last decade due their advantages in the treatment of complex and multifactorial diseases, since "one drug-one target" therapies have failed in many cases to demonstrate clinical efficacy. In this context, we designed and synthesized potential new small multi-target agents with lipoxygenase (LOX), acetyl cholinesterase (AChE) and lipid peroxidation inhibitory activities, as well as antioxidant activity based on 2-/4- hydroxy-chalcones and the bis -etherified bis -chalcone skeleton...
January 7, 2019: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Ismael Reyes, Niradiz Reyes, Robert Suriano, Codrin Iacob, Nina Suslina, Anthony Policastro, Augustine Moscatello, Stimson Schantz, Raj K Tiwari, Jan Geliebter
BACKGROUND: Thyroid cancer is the most common endocrine malignancy worldwide, with the predominant form papillary thyroid carcinoma (PTC) representing approximately 80% of cases. OBJECTIVE: This study was addressed to identify potential genes and pathways involved in the pathogenesis of PTC and potential novel biomarkers for this disease. METHODS: Gene expression profiling was carried out by DNA microarray technology. Validation of microarray data by qRT-PCR, western blot, and enzyme linked immunosorbent assay was also performed in a selected set of genes and gene products, with the potential to be used as diagnostic or prognostic biomarkers, such as those associated with cell adhesion, extracellular matrix (ECM) remodeling and immune/inflammatory response...
December 22, 2018: Cancer Biomarkers: Section A of Disease Markers
Dmitry V Chistyakov, Ivan S Filimonov, Nadezhda V Azbukina, Sergei V Goriainov, Viktor V Chistyakov, Maksim A Fomich, Andrei V Bekish, Vadim V Shmanai, Marina G Sergeeva, Mikhail S Shchepinov
The synthesis of signal lipids, including eicosanoids, is not fully understood, although it is key to the modulation of various inflammatory states. Recently, isotopologues of essential polyunsaturated fatty acids (PUFAs) deuterated at bis-allylic positions (D-PUFAs) have been proposed as inhibitors of non-enzymatic lipid peroxidation (LPO) in various disease models. Arachidonic acid (AA, 20:4 n-6) is the main precursor to several classes of eicosanoids, which are produced by cyclooxygenases (COX) and lipoxygenases (LOX)...
December 15, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Mosad A Ghareeb, Mansour Sobeh, Samar Rezq, Assem M El-Shazly, Mona F Mahmoud, Michael Wink
Reactive oxygen species (ROS) have been linked to several health conditions, among them inflammation. Natural antioxidants may attenuate this damage. Our study aimed to investigate the chemical composition of a methanol leaf extract from Alpinia zerumbet and its possible antioxidant, anti-inflammatory, anti-nociceptive, and antipyretic effects. Altogether, 37 compounds, representing benzoic and cinnamic acid derivatives and flavonoids (aglycones and glycosides), were characterized. The extract showed substantial in vitro antioxidant effects, and inhibited both cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2) in vitro, with a higher selectivity towards COX-2...
December 7, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Evamarie Hey-Hawkins, Robert Kuhnert, Menyhárt-Botond Sárosi, Sven George, Peter Lönnecke, Bettina Hofmann, Dieter Steinhilber, Sara Steinmann, Regine Schneider-Stock, Blagoje Murganic, Sanja Mijatovic, Danijelа Maksimovic-Ivanic
5-Lipoxygenase converts arachidonic acid to leukotrienes that are involved in inflammation and angiogenesis. The introduction of carboranes can improve the pharmacokinetic behavior of metabolically less stable pharmaceutics. We here report the syntheses of several carborane-based inhibitors of the 5-lipoxygenase pathway. The isosteric replacement of phenyl rings by carboranes leads to improved cytotoxicity for several melanoma and colon cancer cell lines. For the colon cancer cell line HCT-116 the co-inhibition of heat shock protein 90 could be detected...
November 24, 2018: ChemMedChem
Atasi De Chatterjee, Debarshi Roy, Priscilla Guevara, Rituraj Pal, Mahesh Naryan, Sukla Roychowdhury, Siddhartha Das
Background: The migration of tumor cells is critical in spreading cancers through the lymphatic nodes and circulatory systems. Although arachidonic acid (AA) and its soluble metabolites have been shown to induce the migration of breast and colon cancer cells, the mechanism by which it induces such migration has not been fully understood. Objective: The effect of AA on migratory responses of the MDA-MB-231 cell line (a triple-negative breast cancer cell) was examined and compared with MCF-7 (estrogen-receptor positive) breast cancer cells to elucidate the mechanism of AA-induced migration...
2018: Clinical Cancer Drugs
Yesseny Vásquez-Martínez, Claudia Torrent, Giannina Toledo, Francisco Cabezas, Victoria Espinosa, Margarita Montoya-K, Sophia Mejias, Marcelo Cortez-San Martín, Silvia Sepúlveda-Boza, Carolina Mascayano
We investigated twelve benzyl phenyl ketone derivatives which are synthetic precursors of isoflavonoids that are shown be good 5-hLOX inhibitors, especially those that have the catechol group, but these precursors never have been assayed as 5-hLOX inhibitors being a novelty as inhibitors of the enzyme, due to sharing important structural characteristics. Screening assays, half maximal inhibitory concentration (IC50 ) and kinetic assays of all the studied molecules (5 µg/ml in media assay) showed that 1-(2,4-dihydroxy-3-methylphenyl)-2-(3-chlorophenyl)-ethanone (K205; IC50  = 3...
October 27, 2018: Bioorganic Chemistry
Sasikamon Khophai, Malinee Thanee, Anchalee Techasen, Nisana Namwat, Poramate Klanrit, Attapol Titapun, Apiwat Jarearnrat, Prakasit Sa-Ngiamwibool, Watcharin Loilome
Background: Inflammatory lipid mediators play an important role in several cancer types. Leukotrienes (LTs), pro-inflammatory lipid mediators, are involved in chronic inflammation and cancer progression. They are derived from arachidonic acid by 5-lipoxygenase (5-LOX) activity. On the other hand, 15-lipoxygenase (15-LOX-1) converts LTs into lipoxins (LXs), pro-resolving lipid mediators. LXs are involved in the attenuation of inflammation and cancer development. Purpose: We aimed to investigate the lipid mediator pathways, especially the LTs and LXs pathways, by studying 5-LOX and 15-LOX-1 expression in human cholangiocarcinoma (CCA) tissue...
2018: OncoTargets and Therapy
Marco S Doucet, Jean-Luc Jougleux, Samuel J Poirier, Marc Cormier, Jacob L Leger, Marc E Surette, Nicolas Pichaud, Mohamed Touaibia, Luc H Boudreau
The inflammatory response is necessary for the host's defense against pathogens; however, uncontrolled or unregulated production of eicosanoids has been associated with several types of chronic inflammatory diseases. Thus, it is not surprising that enzymes implicated in the production of eicosanoids have been strategically targeted for potential therapeutic approaches. The 12-hydroxyeicosatetraenoic acid (12(S)-HETE) lipid mediator is among inflammatory molecules that are abundantly produced in various diseases and is primarily biosynthesized via the 12(S)-lipoxygenase (12-LO) pathway...
November 7, 2018: Molecular Pharmacology
Syed Obaidur Rahman, Rakesh Kumar Singh, Salman Hussain, Mohd Akhtar, Abul Kalam Najmi
Cysteinyl leukotrienes (cysLTs) are member of eicosanoid inflammatory lipid mediators family produced by oxidation of arachidonic acid by action of the enzyme 5-lipoxygenase (5-LOX). 5-LOX is activated by enzyme 5-Lipoxygenase-activating protein (FLAP), which further lead to production of cysLTs i.e. leukotriene C4 (LTC4), leukotriene D4 (LTD4) and leukotriene E4 (LTE4). CysLTs then produce their potent inflammatory actions by activating CysLT1 and CysLT2 receptors. Inhibitors of cysLTs are indicated in asthma, allergic rhinitis and other inflammatory disorders...
October 30, 2018: European Journal of Pharmacology
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