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5 lipoxygenase inhibitors

Rajaram Azad, Neela Kishore Babu, Aparna Dutta Gupta, Pallu Reddanna
Premna integrifolia (Agnimantha brihat) is a traditional medicinal plant with a prominent place in Ayurveda, Siddha and Unani systems of medicine. In this study we have evaluated the anti-inflammatory and immunomodulatory properties of the Premna integrifolia root extracts employing cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), and 5-lipoxygenase (5-LOX) enzyme-based assays, lymphocyte proliferation assay, pro-and anti-inflammatory cytokines measurement. Petroleum ether extract (PEE) of Premna integrifolia showed potent inhibition of COX-2 and 5-LOX with IC50 values of 6...
October 16, 2018: Fitoterapia
T K Shameera Ahamed, Vijisha K Rajan, K Sabira, K Muraleedharan
Developments of novel inhibitors to prevent the function of 5-lipoxygenase (5-LOX) proteins that are responsible for a variety of inflammatory and allergic disease are a major challenge in the scientific community. In this study, robust QSAR classification models for predicting 5-LOX activity were developed using machine learning algorithms. The Support Vector Machines (SVM), Logistic Regression, k-Nearest Neighbour (NN) and Decision Trees were adopted to improve the prediction ability of the classification models...
October 5, 2018: Computational Biology and Chemistry
Tiago Rodrigues, Markus Werner, Jakob Roth, Eduardo H G da Cruz, Marta C Marques, Padma Akkapeddi, Susana A Lobo, Andreas Koeberle, Francisco Corzana, Eufrânio N da Silva Júnior, Oliver Werz, Gonçalo J L Bernardes
Using machine learning, targets were identified for β-lapachone. Resorting to biochemical assays, β-lapachone was validated as a potent, ligand efficient, allosteric and reversible modulator of 5-lipoxygenase (5-LO). Moreover, we provide a rationale for 5-LO modulation and show that inhibition of 5-LO is relevant for the anticancer activity of β-lapachone. This work demonstrates the power of machine intelligence to deconvolute complex phenotypes, as an alternative and/or complement to chemoproteomics and as a viable general approach for systems pharmacology studies...
September 14, 2018: Chemical Science
Sabrin R M Ibrahim, Gamal A Mohamed, Rwaida A Al Haidari, Amal A El-Kholy, Mohamed F Zayed, Maan T Khayat
A new peroxy fatty acid, tagetnoic acid (5) [4-((3S,6S)-6-((3E,8E)-octadeca-3,8-dien-1-yl)-3,6-dihydro-1,2-dioxin-3-yl)butanoic acid] and four known metabolites: ecliptal (5-formyl-α-terthiophene) (1), 5-(4-hydroxybut-1-ynyl)-2,2'-bithiophene (2), 22,23-dihydrospinasterone (3), and stigmasterol (4) were separated from the n-hexane fraction of the aerial parts of Tagetes minuta L. (Asteraceae). Their chemical structures were verified using IR, UV, 2D and 1D NMR, and HRMS. Compounds 3-5 displayed potent lipoxygenase inhibitory potential with IC50 s 2...
October 8, 2018: Natural Product Research
Saravanan S Karuppagounder, Lauren Alin, Yingxin Chen, David Brand, Megan W Bourassa, Kristen Dietrich, Cassandra M Wilkinson, Colby A Nadeau, Amit Kumar, Steve Perry, John T Pinto, Victor Darley-Usmar, Stephanie Sanchez, Ginger L Milne, Domenico Pratico, Theodore R Holman, S Thomas Carmichael, Giovanni Coppola, Frederick Colbourne, Rajiv R Ratan
OBJECTIVES: N-acetylcysteine (NAC) is a clinically approved thiol-containing redox modulatory compound currently in trials for many neurological and psychiatric disorders. Although generically labeled as an "antioxidant", poor understanding of its site(s) of action is a barrier to its use in neurological practice. Here, we examined the efficacy and mechanism of action of NAC in rodent models of hemorrhagic stroke. METHODS: Hemin was used to model ferroptosis and hemorrhagic stroke in cultured neurons...
October 7, 2018: Annals of Neurology
Zhan Li, Yue Gao, Cheng Lin, Ronghui Pan, Wenguang Ma, Yunye Zheng, Yajing Guan, Jin Hu
The preservation of seed viability and quality in storage is an important trait both for commercial and germplasm usage. To better explore potential mechanisms of tobacco seed deterioration, seed packed in cloth bag (C) and vacuum bag (V) were stored under room temperature (RT) and low temperature (LT, 18°C), and sampled periodically for laboratory testing. Seed stored in low temperature with vacuum bag (LT/V) owned the highest seed vigour after 25 months of storage and in room temperature with cloth bag (RT/C) lost seed vigour and germination ability after 20-month storage...
2018: Conservation Physiology
Yanzhuo Liu, Honglin Tang, Xiaoxiao Liu, Honglei Chen, Na Feng, Jing Zhang, Chenlong Wang, Miao Qiu, Jing Yang, Xiaoyang Zhou
Cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX), and cytochrome P450 (CYP) 4A-mediated arachidonic acid (AA) metabolism play an essential role in human inflammatory disorders. Blocking COX-2 pathway would shunt AA metabolism to the other pathway, thereby decreasing the efficacy and exacerbating adverse effects. Here we demonstrated that reprogramming COX-2, 5-LOX, and CYP4A-mediated AA metabolism in macrophages by salidroside (Sal) ameliorates monosodium urate (MSU) crystal-induced inflammation. Compared with COX-2 inhibitor celecoxib, Sal (80 mg/kg) presented a superior anti-arthritic profile in MSU crystal-treated rats, accompanied with the decreased expression of COX-2, 5-LOX, and CYP4A and production of prostaglandin E2 (PGE2 ), leukotriene B4 (LTB4 ), and 20-hydroxyeicosatetraenoic acid (20-HETE) in the synovial fluid macrophages...
September 28, 2018: Journal of Leukocyte Biology
Silke Brand, Sayantani Roy, Peter Schröder, Bernd Rathmer, Jessica Roos, Shobhna Kapoor, Sumersing Patil, Claudia Pommerenke, Thorsten Maier, Petra Janning, Sonja Eberth, Dieter Steinhilber, Dennis Schade, Gisbert Schneider, Kamal Kumar, Slava Ziegler, Herbert Waldmann
Identification and validation of the targets of bioactive small molecules identified in cell-based screening is challenging and often meets with failure, calling for the development of new methodology. We demonstrate that a combination of chemical proteomics with in silico target prediction employing the SPiDER method may provide efficient guidance for target candidate selection and prioritization for experimental in-depth evaluation. We identify 5-lipoxygenase (5-LO) as the target of the Wnt pathway inhibitor Lipoxygenin...
September 20, 2018: Cell Chemical Biology
Helmut Pein, Alexia Ville, Simona Pace, Veronika Temml, Ulrike Garscha, Martin Raasch, Khaled Alsabil, Guillaume Viault, Chau-Phi Dinh, David Guilet, Fabiana Troisi, Konstantin Neukirch, Stefanie König, Rosella Bilancia, Birgit Waltenberger, Hermann Stuppner, Maria Wallert, Stefan Lorkowski, Christina Weinigel, Silke Rummler, Marc Birringer, Fiorentina Roviezzo, Lidia Sautebin, Jean-Jacques Helesbeux, Denis Séraphin, Alexander S Mosig, Daniela Schuster, Antonietta Rossi, Pascal Richomme, Oliver Werz, Andreas Koeberle
Systemic vitamin E metabolites have been proposed as signaling molecules, but their physiological role is unknown. Here we show, by library screening of potential human vitamin E metabolites, that long-chain ω-carboxylates are potent allosteric inhibitors of 5-lipoxygenase, a key enzyme in the biosynthesis of chemoattractant and vasoactive leukotrienes. 13-((2R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)-2,6,10-trimethyltridecanoic acid (α-T-13'-COOH) can be synthesized from α-tocopherol in a human liver-on-chip, and is detected in human and mouse plasma at concentrations (8-49 nM) that inhibit 5-lipoxygenase in human leukocytes...
September 20, 2018: Nature Communications
Seung E Baek, So Y Park, Sun S Bae, Koanhoi Kim, Won S Lee, Chi D Kim
Given the importance of high-mobility group box 1 (HMGB1) and 5-lipoxygenase (5-LO) signaling in vascular inflammation, we investigated the role of leukotriene signaling in monocytes on monocyte-to-macrophage differentiation (MMD) induced by HMGB1, and on vascular inflammation and subsequent intimal hyperplasia in a mouse model of wire-injured femoral artery. In cultured primary bone marrow-derived cells (BMDCs) stimulated with HMGB1, the number of cells with macrophage-like morphology was markedly increased in association with an increased expression of CD11b/Mac-1, which were attenuated in cells pre-treated with Zileuton, a 5-LO inhibitor as well as in 5-LO-deficient BMDCs...
2018: Frontiers in Immunology
Shweta Sinha, Mukesh Doble, S L Manju
Human 5-Lipoxygenase (5-LOX) is a key enzyme targeted for asthma and inflammation. Zileuton, the only drug against 5-LOX, was withdrawn from the market due to several problems. In the present study, the performance of rationally designed conjugates of thiazole (2) and thiourea (3) scaffolds from our previously reported 2-amino-4-aryl thiazole (1) is reported. They are synthesized (total 31 derivatives), characterized, and tested against the 5-LOX enzyme in vitro and the mode of action of the most active ones are determined...
September 3, 2018: European Journal of Medicinal Chemistry
Hamid Sadeghian, Seyed Mohammad Seyedi, Zeinab Jafari
Objectives: 15-Lipoxygenases are one of the iron-containing proteins capable of performing peroxidation of unsaturated fatty acids in animals and plants. The critical role of enzymes in the formation of inflammations, sensitivities, and some cancers has been demonstrated in mammals. The importance of enzymes has led to the development of mechanistic studies, product analysis, and synthesis of inhibitors. Materials and Methods: The inhibitory activity of all synthetic compounds against SLO (soybean 15-lipoxygenase: L1; EC 1,13,11,12) was determined using the peroxide formation method...
July 2018: Iranian Journal of Basic Medical Sciences
Hou-Chuan Lai, Chueng-He Lu, Chih-Shung Wong, Bo-Feng Lin, Shun-Ming Chan, Chan-Yang Kuo, Zhi-Fu Wu
BACKGROUND: Modulating the inflammatory response to nerve injury may provide therapeutic opportunities by aborting the neurobiological alterations that support the development of persistent pain. Baicalein, a 12-lipoxygenase inhibitor, has anti-inflammation properties. It also demonstrates anti-inflammatory functions by inhibiting lipopolysaccharide-induced barrier disruption, expression of cell adhesion molecules, and adhesion and migration of leukocytes. The aim of the present study was to assess the possibility of early treatment of neuropathic pain via the systemic injection of baicalein in rats with left partial sciatic nerve transection (PST)...
August 20, 2018: Journal of the Chinese Medical Association: JCMA
Anne-Sophie Archambault, Caroline Turcotte, Cyril Martin, Véronique Provost, Marie-Chantal Larose, Catherine Laprise, Jamila Chakir, Élyse Bissonnette, Michel Laviolette, Ynuk Bossé, Nicolas Flamand
Neutrophils and eosinophils are important sources of bioactive lipids from the 5- and the 15-lipoxygenase (LO) pathways. Herein, we compared the effectiveness of humans eosinophils and eosinophil-depleted neutrophils to synthesize 15-LO metabolites using a cocktail of different 15-LO substrates as well as their sensitivities to eight documented 15-lipoxygenase inhibitors. The treatment of neutrophils and eosinophils with linoleic acid, dihomo-γ-linolenic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid and arachidonyl-ethanolamide, led to the synthesis of 13-HODE, 15-HETrE, 15-HETE, 15-HEPE, 14-HDHA/17-HDHA, and 15-hydroxy-AEA...
2018: PloS One
Minh Anh Thu Phan, Martin Bucknall, Jayashree Arcot
The interactive effects on anti-oxidation and anti-inflammation of lutein combined with each of the six common anthocyanidin glucosides were studied in both chemical and cellular systems. The combined phytochemicals showed an antagonism in the inhibition of lipid oxidation in a liposomal membrane, but showed an additive effect on cellular antioxidant activity in Caco-2 cells. Lutein was an active lipoxygenase inhibitor at 2⁻12 μM while anthocyanins were inactive. The concentration of lutein when it was used in combination with anthocyanins was 25⁻54% higher than when lutein was used alone (i...
August 14, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Christoph Thiel, Ines Smit, Vanessa Baier, Henrik Cordes, Brigida Fabry, Lars Mathias Blank, Lars Kuepfer
A quantitative analysis of dose-response relationships is essential in preclinical and clinical drug development in order to optimize drug efficacy and safety, respectively. However, there is a lack of quantitative understanding about the dynamics of pharmacological drug-target interactions in biological systems. In this study, a quantitative systems pharmacology (QSP) approach is applied to quantify the drug efficacy of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) inhibitors by coupling physiologically based pharmacokinetic models, at the whole-body level, with affected biological networks, at the cellular scale...
2018: NPJ Systems Biology and Applications
Fatima Naaz, M C Preeti Pallavi, Syed Shafi, Naveen Mulakayala, M Shahar Yar, H M Sampath Kumar
To evaluate the role of COX-2 and 5-LOX as dual inhibitors in controlling the cancer cell proliferation, a set of two series having 42 compounds of 1, 2, 3-Tethered Indole-3-glyoxamide derivatives were synthesized by employing click chemistry approach and were also evaluated for their in vitro cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX) inhibitory activities with in vivo anti-inflammatory and in vitro anti-proliferative potencies. Among the compounds tested, compounds 11q and 13s displayed excellent inhibition of COX-2 (IC50 0...
July 27, 2018: Bioorganic Chemistry
Dušica Simijonović, Evangelia-Eirini Vlachou, Zorica D Petrović, Dimitra J Hadjipavlou-Litina, Κonstantinos E Litinas, Nevena Stanković, Nezrina Mihović, Milan P Mladenović
Dicoumarol derivatives were synthesized in the InCl3 catalyzed pseudo three-component reactions of 4-hydroxycoumarin with aromatic aldehydes in excellent yields. The reactions were performed in water under microwave irradiation. All synthesized compounds were characterized using NMR, IR, and UV-Vis spectroscopy, as well as with TD-DFT. Obtained dicoumarols were subjected to evaluation of their in vitro lipid peroxidation and soybean lipoxygenase inhibition activities. It was shown that five of ten examined compounds (3e, 3h, 3b, 3d, 3f) possess significant potential of antilipid peroxidation (84-97%), and that compounds 3b, 3e, 3h provided the highest soybean lipoxygenase (LOX-Ib) inhibition (IC50  = 52...
October 2018: Bioorganic Chemistry
Sun-Yee Cheung, Markus Werner, Lucia Esposito, Fabiana Troisi, Vincenza Cantone, Stefanie Liening, Stefanie König, Jana Gerstmeier, Andreas Koeberle, Rossella Bilancia, Roberta Rizza, Antonietta Rossi, Fiorentina Roviezzo, Veronika Temml, Daniela Schuster, Hermann Stuppner, Manfred Schubert-Zsilavecz, Oliver Werz, Thomas Hanke, Simona Pace
Leukotrienes (LTs) and prostaglandin (PG)E2 , produced by 5-lipoxygenase (5-LO) and microsomal prostaglandin E2 synthase-1 (mPGES-1), respectively, are key players in inflammation, and pharmacological suppression of these lipid mediators (LM) represents a strategy to intervene with inflammatory disorders. Previous studies revealed that the benzenesulfonamide scaffold displays efficient 5-LO-inhibitory properties. Here, we structurally optimized benzenesulfonamides which led to an N-phenylbenzenesulfonamide derivative (compound 47) with potent inhibitory activities (IC50  = 2...
August 5, 2018: European Journal of Medicinal Chemistry
Ferdinando Bruno, Suann Errico, Simona Pace, Maxim B Nawrozkij, Arthur S Mkrtchyan, Francesca Guida, Rosa Maisto, Abdurrahman Olgaç, Michele D'Amico, Sabatino Maione, Mario De Rosa, Erden Banoglu, Oliver Werz, Antonio Fiorentino, Rosanna Filosa
The release of pro-inflammatory mediators, such as prostaglandines (PGs) and leukotrienes (LTs), arising from the arachidonic acid (AA) cascade, play a crucial role in initiating, maintaining, and regulating inflammatory processes. New dual inhibitors of 5-lipoxygenase (5-LO) and microsomal prostaglandin E2 synthase-1 (mPGES-1), that block, at the same time, the formation of PGE2 and LTs, are currently emerged as a highly interesting drug candidates for better pharmacotherapie of inflammation-related disorders...
July 15, 2018: European Journal of Medicinal Chemistry
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