5-lipoxygenase-in-3

5-Lipoxygenase-IN-3 (Compound 14) 是一种5-Lipoxygenase 抑制剂 (IC50: <1 μM)。5-Lipoxygenase-IN-3 可用于炎症性疾病、癌症、中风和阿尔茨海默病的研究。

Lycopodine, a bioactive compound derived from Lycopodium clavatum spores, effectively inhibits the proliferation of HeLa cells through the induction of apoptosis. This process is mediated by caspase-3 activation. In refractory prostate cancer cells, Lycopodine triggers apoptosis by modulating 5-lipoxygenase and depolarizing the mitochondrial membrane potential, without altering p53 activity.

Lipoxygenin is an inhibitor of 5-lipoxygenase (5-LO) with an IC50value of 5 μM for inhibition of 5-LO product synthesis in isolated human granulocytes stimulated with the cation ionophore A23187 .1It inhibits hedgehog-dependent signaling in Shh-LIGHT2 cells and TGF-β-, activin A-, bone morphogenic protein (BMP)-, or Wnt-dependent signaling in HEK293T cells (IC50s = 9.3, 3.2, 8.2, 9.6, and 3.7 μM, respectively, in luciferase reporter assays). Lipoxygenin (5 and 10 μM) increases levels of troponin T (TnnT), a marker of cardiomyocyte differentiation, in human induced pluripotent stem cells (iPSCs) stimulated with BMP4 and the glycogen synthase kinase 3 (GSK3) inhibitor CHIR99021 .

Myxochelin A is a microbial metabolite that has been found inA. disciformisand has diverse biological activities.1It is active against Gram-positive bacteria, includingB. cereus,S. aureus, andM. luteus, but not Gram-negative bacteria or fungi in an agar diffusion assay when used at a concentration of 80 μg disc. Myxochelin A inhibits 5-lipoxygenase (5-LO) activity with an IC50value of 1.9 μM for the recombinant human enzyme.2It is cytotoxic to 26-L5 colon cancer cells when used at a concentration of 3 μg ml.3

Resolvin E2 (RvE2) is a member of the specialized pro-resolving mediator (SPM) family of bioactive lipids.1It is produced from eicosapentaenoic acidviaan 18-HEPE intermediate, which is formed by aspirin-acetylated COX-2-mediated oxidation of EPA, by 5-lipoxygenase (5-LO) in human polymorphonuclear (PMN) neutrophils.2,3RvE2 (20 ng/animal) inhibits increases in inflammatory exudate neutrophil infiltration in a mouse model of peritonitis induced by zymosan A .3Hepatic RvE2 levels are increased in mice fed normal chow, as well as in a mouse model of high-fat diet-induced non-alcoholic fatty liver disease (NAFLD), by dietary supplementation with EPA.4Plasma levels of RvE2 are increased by dietary supplementation with fish oil containing ω-3 polyunsaturated fatty acids (PUFAs) in patients with peripheral artery disease or chronic kidney disease.1,5,6 1.Chiang, N., and Serhan, C.N.Specialized pro-resolving mediator network: An update on production and actionsEssays Biochem.64(3)443-462(2020) 2.Tjonahen, E., Oh, S.F., Siegelman, J., et al.Resolvin E2: Identification and anti-inflammatory actions: Pivotal role of human 5-lipoxygenase in resolvin E series biosynthesisChemistry & Biology131193-1202(2006) 3.Sungwhan, F.O., Pillai, P.S., Recchiuti, A., et al.Pro-resolving actions and stereoselective biosynthesis of 18S E-series resolvins in human leukocytes and murine inflammationJ. Clin. Invest.121(2)569-581(2011) 4.Echeverría, F., Valenzuela, R., Espinosa, A., et al.Reduction of high-fat diet-induced liver proinflammatory state by eicosapentaenoic acid plus hydroxytyrosol supplementation: Involvement of resolvins RvE1/2 and RvD1/2J. Nutr. Biochem.6335-43(2019) 5.Ramirez, J.L., Gasper, W.J., Khetani, S.A., et al.Fish oil increases specialized pro-resolving lipid mediators in PAD (the OMEGA-PAD II trial)J. Surg. Res.238164-174(2019) 6.Barden, A.E., Shinde, S., Burke, V., et al.The effect of n-3 fatty acids and coenzyme Q10 supplementation on neutrophil leukotrienes, mediators of inflammation resolution and myeloperoxidase in chronic kidney diseaseProstaglandins Other Lipid Mediat.1361-8(2018)

Resolvins are a family of potent lipid mediators derived from both eicosapentaenoic acid and docosahexaenoic acid.[1] In addition to being anti-inflammatory, resolvins promote the resolution of the inflammatory response back to a non-inflamed state.[2] Resolvin D1 is produced physiologically from the sequential oxygenation of DHA by 15- and 5-lipoxygenase.[1] 17(R)-RvD1 is an aspirin-triggered epimer of RvD1 that reduces human polymorphonuclear leukocyte (PMN) transendothelial migration, the earliest event in acute inflammation, with equipotency to RvD1 (EC50 = ~30 nM).[3] 17(R)-RvD1 exhibits a dose-dependent reduction in leukocyte infiltration in a mouse model of peritonitis with maximal inhibition of ~35% at a 100 ng dose.[3] In contrast to RvD1, the aspirin-triggered form resists rapid inactivation by eicosanoid oxidoreductases. Analytical and biological comparisons of synthetic 17(R)-RvD1 with endogenously derived 17(R)-RvD1 have confirmed its identity as matching the natural product.[4]

Dual cyclooxygenase-2 (COX-2) 5-lipoxygenase (5-LO) inhibitors are potential therapeutic agents for inflammatory diseases and for prostate cancer. CAY10416 is a dual COX-2 5-LO inhibitor with IC50 values of 50 and 3 nM, respectively. The selectivity of CAY10416 for COX is greater than 200-fold for COX-2 versus COX-1. COX-2 5-LO inhibitors such as CAY10416 are also apoptosis-inducing agents and are potentially useful in prostate cancer chemotherapy. In the PC3 human carcinoma cell line, CAY10416 exhibits a 45% inhibition of proliferation at 100 μM. In the LNCaP human carcinoma cell line, CAY10416 inhibits growth with an IC50 value of 83 μM.

Resolvin conjugate in tissue regeneration 1 (RCTR1) is a specialized pro-resolving mediator (SPM) biosynthesized from docosahexaenoic acid by isolated human macrophages and apoptotic polymorphonuclear (PMN) neutrophils.1It has been found in human spleen and bone marrow.2RCTR1 is produced via lipoxygenase-mediated oxidation of DHA to 7(S)-8-epoxy-17(S)-HDHA, which is conjugated to glutathione.1,2,3RCTR1 (10 nM) increases phagocytosis ofE. colior apoptotic neutrophils in isolated human monocyte-derived macrophages.2It decreases chemotaxis induced by leukotriene B4in isolated human neutrophils when used at a concentration of 10 nM. RCTR1 (1 and 10 nM) accelerates tissue regeneration in planaria. Intraperitoneal administration of RCTR1 (100 ng/animal) shortens the inflammatory resolution period and decreases inflammatory exudate neutrophil infiltration in a mouse model ofE. coli-induced peritonitis. 1.Dalli, J., Ramon, S., Norris, P.C., et al.Novel proresolving and tissue-regenerative resolvin and protectin sulfido-conjugated pathwaysFASEB J.29(5)2120-2136(2015) 2.de la Rosa, X., Norris, P.C., Chiang, N., et al.Identification and complete stereochemical assignments of the new resolvin conjugates in tissue regeneration in human tissues that stimulate proresolving phagocyte functions and tissue regenerationAm. J. Pathol.188(4)950-966(2018) 3.Rodriguez, A.R., and Spur, B.W.First total synthesis of pro-resolving and tissue-regenerative resolvin sulfido-conjugatesTetrahedron Lett.58(16)1662-1668(2017)

9(S),12(S),13(S)-TriHOME is a linoleic acid-derived oxylipin that has diverse biological activities.1,2,3,4It has been found in various plants and is produced in human eosinophils in a 15-lipoxygenase-dependent, soluble epoxide hydrolase-independent manner.1,59(S),12(S)13(S)-TriHOME inhibits antigen-induced β-hexosaminidase release from RBL-2H3 mast cells (IC50= 28.7 μg ml).2It inhibits LPS-induced nitric oxide (NO) production in BV-2 microglia (IC50= 40.95 μM).3In vivo, 9(S),12(S),13(S)-TriHOME (1 g animal) enhances the antiviral IgA and IgG antibody responses induced by a nasal influenza hemagglutinin (HA) vaccine by 5.2- and 2-fold, respectively, in mice.4 1.Hamberg, M., and Hamberg, G.Peroxygenase-catalyzed fatty acid epoxidation in cereal seeds: Sequential oxidation of linoleic acid into 9(S),12(S),13(S)-trihydroxy-10(E)-octadecenoic acidPlant Physiol.110(3)807-815(1996) 2.Hong, S.S., and Oh, J.S.Inhibitors of antigen-induced degranulation of RBL-2H3 cells isolated from wheat branJ. Korean Soc. Appl. Biol. Chem.5569-74(2012) 3.Kim, C.S., Kwon, O.W., Kim, S.Y., et al.Five new oxylipins from Chaenomeles sinensisLipids49(11)1151-1159(2014) 4.Shirahata, T., Sunazuka, T., Yoshida, K., et al.Total synthesis, elucidation of absolute stereochemistry, and adjuvant activity of trihydroxy fatty acidsTetrahedron62(40)9483-9496(2006) 5.Fuchs, D., Tang, X., Johnsson, A.-K., et al.Eosinophils synthesize trihydroxyoctadecenoic acids (TriHOMEs) via a 15-lipoxygenase dependent processBiochim. Biophys. Acta Mol. Cell Biol. Lipids1865(4)158611(2020)

Docosapentaenoic acid (DPA) is a ω-3 fatty acid found in fish oils. 17-oxo-7(Z),10(Z),13(Z),15(E),19(Z)-docosapentaenoic acid is a metabolite of lipoxygenase-mediated oxidation of DPA that is produced endogenously by aspirin-enhanced COX-2 activity. It has been shown to activate Nrf2-dependent antioxidant gene expression, to act as a PPARγ agonist (EC50 = ~200 nM), and to inhibit pro-inflammatory cytokine and nitric oxide production at biological concentration ranges (5-25 μM).

12(S)-HEPE is a monohydroxy fatty acid synthesized from EPA by the action of 12-LO. Unstimulated neutrophils metabolize 12(S)-HEPE to 12(S),20-diHEPE, whereas stimulated neutrophils produce 5(S),12(S)-HEPE via the 5-lipoxygenase pathway. The competitive action of 12(S)-HEPE with arachidonic acid as a substrate for 5-LO in the formation of leukotrienes may provide a basis for the anti-inflammatory potential of ω-3 fatty acids.

12-oxo-13-HOME is an oxylipin derived from linoleic acid .1It is formedviaa 13-HpODE intermediate that is produced by lipoxygenase-mediated metabolism of linoleic acid.2,3,112-oxo-13-HOME has been found in corn and sunflower seedlings.4 1.Ogorodnikova, A.V., Gorina, S.S., Mukhtarova, L.S., et al.Stereospecific biosynthesis of (9S,13S)-10-oxo-phytoenoic acid in young maize rootsBiochim. Biophys. Acta1851(9)1262-1270(2015) 2.Veldink, G.A., and Vliegenthart, J.F.G.The enzymic conversions of 13-hydroperoxy-cis-9-trans-11-octadecadienoic acid into 13-hydroxy-12-oxo-cis-9-octadecenoic acidBiochem. J.110(4)58P(1968) 3.Gardner, H.W.Sequential enzymes of linoleic acid oxidation in corn germ: Lipoxygenase and linoleate hydroperoxide isomeraseJ. Lipid Res.11(4)311-321(1970) 4.Vick, B.A., and Zimmerman, D.C.Levels of oxygenated fatty acids in young corn and sunflower plantsPlant Physiol.69(5)1103-1108(1982)

Heneicosapentaenoic Acid (HPA) is a 21:5 ω-3 fatty acid present in trace amounts in the green alga B. pennata and in fish oils. Its chemical composition is similar to eicosapentaenoic acid (EPA) except elongated with one carbon on the carboxyl end, placing the first double bond in the δ6 position. HPA can be used to study the significance of the position of the double bonds in ω-3 fatty acids. It incorporates into phospholipids and into triacylglycerol in vivo with the same efficiency as EPA and docosahexaenoic acid and exhibits strong inhibition of arachidonic acid synthesis from linoleic acid. HPA is a poor substrate for prostaglandin H synthase (PGHS) (cyclooxygenase) and for 5-lipoxygenase but retains the ability to rapidly inactivate PGHS.

Prostaglandin E2抑制剂3是一种microsomal prostaglandin E合酶-1 (mPGES-1; IC50 = 0.2 µM)的抑制剂，相较于COX-1、COX-2、5-lipoxygenase (5-LO)和soluble epoxide hydrolase (sEH)，在10 µM的无细胞试验中表现出对mPGES-1的选择性。在10 µM和1 µM的浓度下，该抑制剂能抑制A549细胞中IL-1β诱导的PGE2生成以及在J774A.1巨噬细胞中，LPS诱导的IL-6和PGE2生成。同时，它还能抑制由钙离子载体A23187单独或结合花生四烯酸和A23187诱导的5-LO产物形成，包括白三烯B4 (LTB4) 和5-H(p)ETE（IC50s分别为4.9和5.2 µM）。在体内，10 mg/kg剂量的Prostaglandin E2抑制剂3能防止在zymosan诱导的小鼠腹膜炎模型中白细胞渗入腹腔液中。

Heneicosapentaenoic Acid (HPA) is a fatty acid found in small amounts in Bryopsis pennata Lamouroux green algae and fish oils, with a structure similar to eicosapentaenoic acid (EPA), but with an additional carbon at the carboxyl end, resulting in the first double bond being in the Δ6 position. HPA is important for researching the impact of double bond positions in n-3 fatty acids, as it integrates into phospholipids and triacylglycerol in vivo as effectively as EPA and docosahexaenoic acid (DHA), while strongly inhibiting the synthesis of arachidonic acid from linoleic acid. Despite being a poor substrate for prostaglandin H (PGH) synthase and 5-lipoxygenase, HPA can rapidly deactivate PGH synthase. HPA methyl ester, in certain formulations, acts as a prodrug to enhance cellular uptake of HPA before being converted into free acid by esterases, and serves as a useful reference standard.

Phenethyl ferulate (Caffeic Acid 3-Methyl Phenethyl Ester) 对化学诱导的结肠癌具有化学预防特性，可增强偶氮甲烷诱导的结肠肿瘤的细胞凋亡。 它抑制环氧合酶(COX) 和 5-脂氧合酶 (5-LOX) ，IC50 值分别为 4.35 和 5.75 μM。