5 lipoxygenase inhibitors

BACKGROUND: The aleurone layer is a part of many plant seeds, and during seed germination, aleurone cells undergo PCD, which is promoted by GA from the embryo. However, the numerous components of the GA signaling pathway that mediate PCD of the aleurone layers remain to be identified. Few genes and transcriptomes have been studied thus far in aleurone layers to improve our understanding of how PCD occurs and how the regulatory mechanism functions during PCD. Our previous studies have shown that histone deacetylases (HDACs) are required in GA-induced PCD of aleurone layer...

The thiophene bearing pyrazole derivatives (7a-j) were synthesized and examined for their in vitro cyclooxygenase, 5-lipoxygenase, and tumour inducing factor-α inhibitory activities followed by the in vivo analgesic, anti-inflammatory, and ulcerogenic evaluations. The synthesized series (7a-j) were characterized using 1 H NMR, 13 C NMR, FT-IR, and mass spectral analysis. Initially, the compounds (7a-j) were evaluated for their in vitro cyclooxygenase, 5-lipoxygenase, and tumour inducing factor-α inhibitory activities and the compound (7f) with two phenyl substituents in the pyrazole ring and chloro substituent in the thiophene ring and the compound (7g) with two phenyl substituents in the pyrazole ring and bromo substituent in the thiophene ring were observed as potent compounds among the series...

Inflammation is a multifaceted biological process in which the conversion of arachidonic acid to eicosanoids, including prostaglandins and leukotrienes (LTs), plays a crucial role. 5-Lipoxygenase (5-LOX) is a key enzyme in cellular LT biosynthesis, and it is supported by the accessory protein 5-lipoxygenase-activating protein (FLAP). Pharmacological interventions to modulate LTs aim at either decreasing their biosynthesis or at mitigating their biological effects. Therefore, inhibiting 5-LOX or FLAP represents a useful strategy to reduce inflammation...

This study explored new methods to inhibit human 5-lipoxygenase (5-hLOX) by analyzing natural terpenes that share structural similarities with acetoxyboswellic acid (AKBA). Enzymatic assays were used to evaluate the terpene's ability to inhibit the enzyme, potentially providing anti-inflammatory benefits. Our research focused on how certain types of triterpenes can inhibit 5-hLOX allosterically via a newly discovered allosteric site identified by enzyme crystallization. To determine whether natural boswellic acid analogs mimicked the allosteric known inhibitor AKBA, we combined 5-hLOX inhibition with in silico modeling...

Exacerbated inflammatory responses are a hallmark of severe coronavirus disease 2019 (COVID-19). Zileuton (Zi) is a selective inhibitor of 5-lipoxygenase, an enzyme involved in the production of several inflammatory/pro-resolving lipid mediators. Herein, we investigated the effect of Zi treatment in a severe acute respiratory syndrome (SARS) model. Mouse hepatitis virus (MHV)3-infected mice treated with Zi significantly improved the clinical score, weight loss, cardiopulmonary function, and survival rates compared with infected untreated animals...

The three primary enzymes COX (cyclooxygenase), LOX (lipoxygenase) and CYT-P450 (cytochrome P450), which are part of the arachidonic inflammatory pathway, play crucial role in the development of asthma, rheumatoid arthritis and cardiovascular diseases. Ethnomedicinally, plant-derived chemicals have a major role in the treatment of fatal illnesses. Aquilaria malaccensis Lam. widely known as agarwood is prized for its fragrance and therapeutic properties. The phytochemicals and extracts of this plant have significant healing properties in the treatment of serious illnesses...

Objective To investigate the effects of YAP on the occurrence and progression of acute liver failure by regulating the ferroptosis pathway and its underlying mechanism. Methods A total of 20 8-week-old C57BL/6 mice were randomly divided into four groups: a control group, an acute liver failure model group, a YAP agonist XMU-MP-1 treatment group and a YAP inhibitor verteporfin treatment group, five mice for each group. HE staining was used to observe the pathological changes of hepatic inflammation and necrosis...

OBJECTIVE AND DESIGN: 15-Lipoxygenase-1 (15-LOX-1) catalyzes the biosynthesis of many anti-inflammatory and immunomodulatory lipid mediators and was reported to have protective properties in several inflammatory conditions, including osteoarthritis (OA). This study was designed to evaluate the expression of 15-LOX-1 in cartilage from normal donors and patients with OA, and to determine whether it is regulated by DNA methylation. METHODS: Cartilage samples were obtained at autopsy from normal knee joints and from OA-affected joints at the time of total knee joint replacement surgery...

Synaptosomes offer an intriguing ex vivo model system for investigating the molecular mechanisms of neurodegenerative processes. Lipoxygenases significantly affect the course of neurodegenerative diseases. Homeostasis of trace elements such as zinc is necessary for the continuity of brain functions. In this study, we purpose to determine whether LOXBlock-1, a 12/15 lipoxygenase inhibitor, and zinc sulfate (ZnSO4 ) provide any biochemical protection during neurodegenerative damage in synaptosomes induced by amyloid beta 1-42 (Aβ1-42)...

Arachidonic acid (AA), an n-6 essential fatty acid, is a major component of mammalian cells and can be released by phospholipase A2. Accumulating evidence indicates that AA plays essential biochemical roles, as it is the direct precursor of bioactive lipid metabolites of eicosanoids such as prostaglandins, leukotrienes, and epoxyeicosatrienoic acid obtained from three distinct enzymatic metabolic pathways: the cyclooxygenase pathway, lipoxygenase pathway, and cytochrome P450 pathway. AA metabolism is involved not only in cell differentiation, tissue development, and organ function but also in the progression of diseases, such as hepatic fibrosis, neurodegeneration, obesity, diabetes, and cancers...

Global burden of breast cancer is expected to cross 26 million new cases by 2030. The term 'triple negative breast cancer' (TNBC) refers to lack of expression of hormone receptors (ER, PR and HER2). 5-Lipoxygenase (5-LOX) inhibition promotes breast cancer apoptosis, ferroptosis and inhibits metastases. Nuclear factor kappa B (NF-κB) activation induces cell survival in breast cancer through stimulation of angiogenesis. Therefore, inhibiting NF-B signalling can stop the growth of tumours. In light of these facts, an attempt is made to investigate binding characteristics of LOX inhibitors against 5-LOX (PDB-IDs 3V99 and 6N2W) and NF-κB (PDB-IDs 4KIK and 3DO7) through molecular docking, MM-GBSA calculation, molecular dynamic simulations (MDSs) and drug-likeness analysis...

Sensitizing strategy is required to improve the clinical management of glioblastoma (GBM). 5-Lipoxygenase (Alox5) has been recently garnered attention due to its pro-carcinogenic roles in various cancers. This study demonstrates that Alox5 is overexpressed in GBM but not normal neuronal tissues. Alox5 depletion inhibits the growth of GBM cells, both in bulky and stem-like populations, and enhances the anti-cancer effects of temozolomide. The mechanism behind this involves a decrease in β-catenin level and activity upon Alox5 depletion...

Lipoxygenases (LOX) transform arachidonic acid (AA, C20:4) and docosahexaenoic acid (DHA, C22:6) into bioactive lipid mediators (LMs) that comprise not only pro-inflammatory leukotrienes (LTs) but also the specialized pro-resolving mediators (SPMs) that promote inflammation resolution and tissue regeneration. The 5-LOX-activating protein (FLAP) is known to provide AA as a substrate to 5-LOX for generating LTs, such as LTB4 , a potent chemoattractant and activator of phagocytes. Notably, 5-LOX is also involved in the biosynthesis of certain SPMs, namely, lipoxins and D-resolvins, implying a role of FLAP in SPM formation...

5-Lipoxygenase-activating protein (FLAP) is a regulator of cellular leukotriene biosynthesis, which governs the transfer of arachidonic acid (AA) to 5-lipoxygenase for efficient metabolism. Here, the synthesis and FLAP-antagonistic potential of fast synthetically accessible 1,2,4-triazole derivatives based on a previously discovered virtual screening hit compound is described. Our findings reveal that simple structural variations on 4,5-diaryl moieties and the 3-thioether side chain of the 1,2,4-triazole scaffold markedly influence the inhibitory potential, highlighting the significant chemical features necessary for FLAP antagonism...

BACKGROUND: Platelets for transfusion are stored for 5 to 7 days. Previous studies have shown that HETE levels in the storage bag negatively correlate with platelet performance in vivo, suggesting that the dysregulation of bioactive lipid mediators may contribute to the storage lesion. In the current study, we sought to understand how genetic deletion and pharmacological inhibition of 12-LOX (12-lipoxygenase) affects platelets during storage and after transfusion. METHODS: Platelets from 12-LOX+/+ (wild-type [WT]) and 12-LOX-/- mice were stored for 24 and 48 hours and profiled using liquid chromatography-tandem mass spectrometry-multiple reaction monitoring or transfused into thrombocytopenic hIL4R-transgenic mice...

Simplified analogues of the myxobacterial polyketide ajudazol were obtained by synthesis and evaluated for their biological activities. Potent simplified 5-lipoxygenase inhibitors were identified. Moreover, strong antiproliferative and apoptotic activities were observed in brain cancer cell lines at low nano- to micromolar concentrations.

We report here small molecules consisting of dichlorophenyl substituted oxindole that is further tagged with pyrrole/indole moieties. These molecules were designed on the basis of the analysis of binding mode of 5-LOX with arachidonic acid and zileuton. The molecules traverse the active site pocket of the enzyme that otherwise hosts AA and zileuton. Moreover, with a provision of derivatization at pyrrole/indole-N, the physico-chemical properties of the molecules can be adjusted. Appreciable 5-LOX inhibitory activities of the compounds in sub-micromolar range were observed and their aqueous solubility, binding with human serum albumin and stability in blood plasma and liver microsomes were checked...

Mammalian 15-lipoxygenases (ALOX15) are lipid peroxidizing enzymes that exhibit variable functionality in different cancer and inflammation models. The pathophysiological role of linoleic acid- and arachidonic acid-derived ALOX15 metabolites rendered this enzyme a target for pharmacological research. Several indole and imidazole derivatives inhibit the catalytic activity of rabbit ALOX15 in a substrate-specific manner, but the molecular basis for this allosteric inhibition remains unclear. Here, we attempt to define a common pharmacophore, which is critical for this allosteric inhibition...

Eicosanoids are a family of bioactive lipids that play diverse roles in the normal physiology of the brain, including neuronal signaling, synaptic plasticity, and regulation of cerebral blood flow. In the brain, eicosanoids are primarily derived from arachidonic acid, which is released from membrane phospholipids in response to various stimuli. Prostaglandins (PGs) and leukotrienes (LTs) are the major classes of eicosanoids produced in the brain, and they act through specific receptors to modulate various physiological and pathological processes...

Lipid metabolism is a complex process crucial for energy production resulting in high levels of acyl-coenzyme A (acyl-CoA) molecules in the cell. Acyl-CoAs have also been implicated in inflammation, which could be possibly linked to lipoxygenase (LOX) biochemistry by the observation that an acyl-CoA was bound to human platelet 12-lipoxygenase via cryo-EM. Given that LOX isozymes play a pivotal role in inflammation, a more thorough investigation of the inhibitory effects of acyl-CoAs on lipoxygenase isozymes was judged to be warranted...