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Christina S Leslie - One of the best experts on this subject based on the ideXlab platform.
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regulation of Cytosolic Phospholipase A2 activation and cyclooxygenase 2 expression in macrophages by the β glucan receptor
Journal of Biological Chemistry, 2006Co-Authors: Saritha Suram, Gordon D Brown, Moumita Ghosh, Siamon Gordon, Robyn Loper, Philip R Taylor, Shizuo Akira, Satoshi Uematsu, David L Williams, Christina S LeslieAbstract:Abstract Phagocytosis of non-opsonized microorganisms by macrophages initiates innate immune responses for host defense against infection. Cytosolic Phospholipase A2 is activated during phagocytosis, releasing arachidonic acid for production of eicosanoids, which initiate acute inflammation. Our objective was to identify pattern recognition receptors that stimulate arachidonic acid release and cyclooxygenase 2 (COX2) expression in macrophages by pathogenic yeast and yeast cell walls. Zymosan- and Candida albicans-stimulated arachidonic acid release from resident mouse peritoneal macrophages was blocked by soluble glucan phosphate. In RAW264.7 cells arachidonic acid release, COX2 expression, and prostaglandin production were enhanced by overexpressing the β-glucan receptor, dectin-1, but not dectin-1 lacking the cytoplasmic tail. Pure particulate (1, 3)-β-d-glucan stimulated arachidonic acid release and COX2 expression, which were augmented in a Toll-like receptor 2 (TLR2)-dependent manner by macrophage-activating lipopeptide-2. However, arachidonic acid release and leukotriene C4 production stimulated by zymosan and C. albicans were TLR2-independent, whereas COX2 expression and prostaglandin production were partially blunted in TLR2–/– macrophages. Inhibition of Syk tyrosine kinase blocked arachidonic acid release and COX2 expression in response to zymosan, C. albicans, and particulate (1, 3)-β-d-glucan. The results suggest that Cytosolic Phospholipase A2 activation triggered by the β-glucan component of yeast is dependent on the immunoreceptor tyrosine-based activation motif-like domain of dectin-1 and activation of Syk kinase, whereas both TLR2 and Syk kinase regulate COX2 expression.
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ceramide 1 phosphate is a direct activator of Cytosolic Phospholipase A2
Journal of Biological Chemistry, 2004Co-Authors: Benjamin J Pettus, Preeti Subramanian, Christina S Leslie, John H Evans, Alicja Bielawska, Dayanjan S Wijesinghe, Michael Maceyka, Jessica Freiberg, Patrick Roddy, Yusuf A HannunAbstract:Abstract Recently, we demonstrated that ceramide kinase, and its product, ceramide 1-phosphate (Cer-1-P), were mediators of arachidonic acid released in cells in response to interleukin-1β and calcium ionophore (Pettus, B. J., Bielawska, A., Spiegel, S., Roddy, P., Hannun, Y. A., and Chalfant, C. E. (2003) J. Biol. Chem. 278, 38206–38213). In this study, we demonstrate that down-regulation of Cytosolic Phospholipase A2 (cPLA2) using RNA interference technology abolished the ability of Cer-1-P to induce arachidonic acid release in A549 cells, demonstrating that cPLA2 is the key Phospholipase A2 downstream of Cer-1-P. Treatment of A549 cells with Cer-1-P (2.5 μm) induced the translocation of full-length cPLA2 from the cytosol to the Golgi apparatus/perinuclear regions, which are known sites of translocation in response to agonists. Cer-1-P also induced the translocation of the CaLB/C2 domain of cPLA2 in the same manner, suggesting that this domain is responsive to Cer-1-P either directly or indirectly. In vitro studies were then conducted to distinguish these two possibilities. In vitro binding studies disclosed that Cer-1-P interacts directly with full-length cPLA2 and with the CaLB domain in a calcium- and lipid-specific manner with a KCa of 1.54 μm. Furthermore, Cer-1-P induced a calcium-dependent increase in cPLA2 enzymatic activity as well as lowering the EC50 of calcium for the enzyme from 191 to 31 nm. This study identifies Cer-1-P as an anionic lipid that translocates and directly activates cPLA2, demonstrating a role for this bioactive lipid in the mediation of inflammatory responses.
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intracellular calcium signals regulating Cytosolic Phospholipase A2 translocation to internal membranes
Journal of Biological Chemistry, 2001Co-Authors: John H Evans, Diane M Spencer, Adam Zweifach, Christina S LeslieAbstract:Abstract Increased intracellular CA2+concentrations ([CA2+]i) promote Cytosolic Phospholipase A2 (cPLA2) translocation to intracellular membranes. The specific membranes to which cPLA2 translocates and the [CA2+]isignals required were investigated. Plasmids of EGFP fused to full-length cPLA2 (EGFP-FL) or to the cPLA2 C2 domain (EGFP-C2) were used in CA2+/EGFP imaging experiments of cells treated with [CA2+]i-mobilizing agonists. EGFP-FL and -C2 translocated to Golgi in response to sustained [CA2+]i greater than ∼100–125 nm and to Golgi, ER, and perinuclear membranes (PNM) at [CA2+]i greater than ∼210–280 nm. In response to short duration [CA2+]i transients, EGFP-C2 translocated to Golgi, ER, and PNM, but EGFP-FL translocation was restricted to Golgi. However, EGFP-FL translocated to Golgi, ER, and PNM in response to long duration transients. In response to declining [CA2+]i, EGFP-C2 readily dissociated from Golgi, but EGFP-FL dissociation was delayed. Agonist-induced arachidonic acid release was proportional to the [CA2+]i and to the extent of cPLA2translocation. In summary, we find that the differential translocation of cPLA2 to Golgi or to ER and PNM is a function of [CA2+]i amplitude and duration. These results suggest that the cPLA2 C2 domain regulates differential, CA2+-dependent membrane targeting and that the catalytic domain regulates both the rate of translocation and enzyme residence.
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Cytosolic Phospholipase A2 is required for macrophage arachidonic acid release by agonists that do and do not mobilize calcium novel role of mitogen activated protein kinase pathways in Cytosolic Phospholipase A2 regulation
Journal of Biological Chemistry, 2000Co-Authors: Miguel A Gijon, Joseph V Bonventre, Diane M Spencer, Abdur R Siddiqi, Christina S LeslieAbstract:Abstract The 85-kDa Cytosolic Phospholipase A2 (cPLA2) mediates agonist-induced arachidonic acid release and eicosanoid production. Calcium and phosphorylation on Ser-505 by mitogen-activated protein kinases (MAPKs) regulate cPLA2. Arachidonic acid release and eicosanoid production induced by stimuli that do (A23187, zymosan) or do not (phorbol myristate acetate (PMA), okadaic acid) mobilize calcium were quantitatively suppressed in cPLA2-deficient mouse peritoneal macrophages. The contribution of MAPKs to cPLA2-mediated arachidonic acid release was investigated. Both extracellular signal-regulated kinases (ERKs) and p38 contributed to cPLA2 phosphorylation on Ser-505. However, although ERK inhibition did not affect A23187-induced arachidonic acid release, it suppressed zymosan-, PMA-, and okadaic acid-induced arachidonic acid release under conditions where phosphorylation of cPLA2 on Ser-505 was unaffected. This indicates an additional regulatory mechanism for the ERK pathway. A role for transcriptional regulation is suggested by data showing that cycloheximide and actinomycin D inhibited arachidonic acid release induced by zymosan, PMA and, okadaic acid but not by A23187. Our results show that MAPK pathways contribute to arachidonic acid release in macrophages through alternative mechanisms in addition to their ability to phosphorylate cPLA2 on Ser-505 and suggest a role for new protein synthesis.
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role of phosphorylation sites and the c2 domain in regulation of Cytosolic Phospholipase A2
Journal of Cell Biology, 1999Co-Authors: Miguel A Gijon, Diane M Spencer, Alan L Kaiser, Christina S LeslieAbstract:Cytosolic Phospholipase A2 (cPLA2) mediates agonist-induced arachidonic acid release, the first step in eicosanoid production. cPLA2 is regulated by phosphorylation and by calcium, which binds to a C2 domain and induces its translocation to membrane. The functional roles of phosphorylation sites and the C2 domain of cPLA2 were investigated. In Sf9 insect cells expressing cPLA2, okadaic acid, and the calcium-mobilizing agonists A23187 and CryIC toxin induce arachidonic acid release and translocation of green fluorescent protein (GFP)-cPLA2 to the nuclear envelope. cPLA2 is phosphorylated on multiple sites in Sf9 cells; however, only S505 phosphorylation partially contributes to cPLA2 activation. Although okadaic acid does not increase calcium, mutating the calcium-binding residues D43 and D93 prevents arachidonic acid release and translocation of cPLA2, demonstrating the requirement for a functional C2 domain. However, the D93N mutant is fully functional with A23187, whereas the D43N mutant is nearly inactive. The C2 domain of cPLA2 linked to GFP translocates to the nuclear envelope with calcium-mobilizing agonists but not with okadaic acid. Consequently, the C2 domain is necessary and sufficient for translocation of cPLA2 to the nuclear envelope when calcium is increased; however, it is required but not sufficient with okadaic acid.
W V Scheuer - One of the best experts on this subject based on the ideXlab platform.
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Activation of Cytosolic Phospholipase A2 in human T-lymphocytes involves inhibitor-κB and mitogen-activated protein kinases
European Journal of Pharmacology, 2003Co-Authors: Elke Burgermeister, Josef Endl, W V ScheuerAbstract:Abstract The group IV 85 kDa Cytosolic Phospholipase A2 regulates many aspects of innate immunity. However, the function of this enzyme in T-cells remains controversial. We show here that human peripheral blood lymphocytes and Jurkat cells express Cytosolic Phospholipase A2 and produce prostaglandin A2 and leukotriene B4. Selective inhibitors of this enzyme suppressed CA2+-ionophore-, mitogen- and T-cell receptor-mediated expression of interleukin-2 at the level of transcription from the promoter. Activation of mitogen-activated protein kinases (MAPK), degradation of inhibitor-κBα and transactivation by nuclear factor-κB (NFκB) were impaired as was the antigen-, lectin- and interleukin-2-driven proliferation of T-cells in vitro. Ligands of peroxisome proliferator-activated receptor-γ (PPARγ) induced rapid phosphorylation of MAPK in human monocytic but not in Jurkat cells. These data indicated that in T-cells, eicosanoids generated upon signal-activated Cytosolic Phospholipase A2 promote NFκB-dependent interleukin-2 transcription via a PPARγ-independent mechanism involving the MAPK-pathway.
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Inhibition of Cytosolic Phospholipase A2 attenuates activation of mitogen-activated protein kinases in human monocytic cells
European Journal of Pharmacology, 2000Co-Authors: Elke Burgermeister, U Tibes, Ulrich Pessara, Andrea Küster, Peter C. Heinrich, W V ScheuerAbstract:Abstract Eicosanoids and platelet-activating factor generated upon activation of Cytosolic Phospholipase A2 enhance activity of transcription factors and synthesis of proinflammatory cytokines. Here, we show that selective inhibitors and antisense oligonucleotides against this enzyme suppressed expression of the interleukin-1β gene at the level of transcription and promoter activation in human monocytic cell lines. This inhibitory effect was due to failure of activation of mitogen-activated protein kinases (MAPK) through phosphorylation by upstream mitogen-activated protein kinase kinases (MKK). Consequently, phosphorylation and degradation of inhibitor-κBα (I-κBα) and subsequent cytoplasmic mobilization, DNA-binding and the transactivating potential of nuclear factor-κB (NF-kB), nuclear factor-interleukin-6 (NF-IL6), activation protein-1 (AP-1) and signal-transducer-and-activator-of-transcription-1 (STAT-1) were impaired. It is concluded, that lipid mediators promote activation of MAPKs, which in turn lead to phosphorylation and liberation of active transcription factors. Since inhibition of Cytosolic Phospholipase A2 ameliorates inflammation in vivo, this potency may reside in interference with the MAPK pathway.
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Activation of nuclear factor-κB by lipopolysaccharide in mononuclear leukocytes is prevented by inhibitors of Cytosolic Phospholipase A2
European Journal of Pharmacology, 1999Co-Authors: Elke Burgermeister, U Tibes, Hubertus Stockinger, W V ScheuerAbstract:Abstract In monocytes, lipopolysaccharide induces synthesis and activity of the 85-kDa Cytosolic Phospholipase A2. This enzyme releases arachidonic acid and lyso-phospholipids from membranes which are metabolized to eicosanoids and platelet-activating-factor. These lipid mediators increase activity of transcription factors and expression of cytokine genes indicating a function for Cytosolic Phospholipase A2 in signal transduction and inflammation. We have shown previously that trifluoromethylketone inhibitors of Cytosolic Phospholipase A2 suppressed interleukin-1β protein and steady-state mRNA levels in human lipopolysaccharide-stimulated peripheral blood mononuclear leukocytes. In this study, the subcellular mechanisms were analyzed by which trifluoromethylketones interfere with gene expression. We found that they reduced the initial interleukin-1β mRNA transcription rate through prevention of degradation of inhibitor-κBα. Consequently, Cytosolic activation, nuclear translocation and DNA-binding of nuclear factor-κB were decreased. Trifluoromethylketones ameliorate chronic inflammation in vivo. Thus, this therapeutic potency may reside in retention of inactive nuclear factor-κB in the cytosol thereby abrogating interleukin-1β gene transcription.
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Suppression of cytokine synthesis, integrin expression and chronic inflammation by inhibitors of Cytosolic Phospholipase A2.
European journal of pharmacology, 1997Co-Authors: E Amandi-burgermeister, U Tibes, B M Kaiser, W G Friebe, W V ScheuerAbstract:To define the isoform of Phospholipases A2 active in inflammation we evaluated the effects of low-molecular-weight inhibitors of secretory and Cytosolic Phospholipases A2. We found that inhibitors of Cytosolic Phospholipase A2 had therapeutic efficacy in an in vivo model of chronic inflammation (rat adjuvant arthritis), whereas inhibitors of secretory Phospholipase A2 had no beneficial effect. In vitro, inhibitors of Cytosolic Phospholipase A2 diminished surface expression of Mac-1 (CD11b/CD18) betA2-integrin on calcium ionophore-stimulated human blood granulocytes and suppressed synthesis of interleukin-1beta in lipopolysaccharide-stimulated human blood monocytes and U937 cells by reducing mRNA levels. Lipid mediators promote Mac-1 exocytosis and transcription of interleukin-1beta, which further enhances Cytosolic Phospholipase A2 activity and expression. Thus, superinduction of Cytosolic Phospholipase A2 may establish a positive feedback loop, converting acute inflammation into chronic inflammation. Consequently, inhibitors of Cytosolic Phospholipase A2 may prevent inflammation in vivo by interfering with cellular activation and infiltration. We conclude that Cytosolic Phospholipase A2 but not secretory Phospholipase A2 is the predominant enzyme in inflammatory signalling.
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Suppression of cytokine synthesis, integrin expression and chronic inflammation by inhibitors of Cytosolic Phospholipase A2
European Journal of Pharmacology, 1997Co-Authors: E Amandi-burgermeister, U Tibes, B M Kaiser, W G Friebe, W V ScheuerAbstract:Abstract To define the isoform of Phospholipases A2 active in inflammation we evaluated the effects of low-molecular-weight inhibitors of secretory and Cytosolic Phospholipases A2. We found that inhibitors of Cytosolic Phospholipase A2 had therapeutic efficacy in an in vivo model of chronic inflammation (rat adjuvant arthritis), whereas inhibitors of secretory Phospholipase A2 had no beneficial effect. In vitro, inhibitors of Cytosolic Phospholipase A2 diminished surface expression of Mac-1 (CD11b/CD18) β2-integrin on calcium ionophore-stimulated human blood granulocytes and suppressed synthesis of interleukin-1β in lipopolysaccharide-stimulated human blood monocytes and U937 cells by reducing mRNA levels. Lipid mediators promote Mac-1 exocytosis and transcription of interleukin-1β, which further enhances Cytosolic Phospholipase A2 activity and expression. Thus, superinduction of Cytosolic Phospholipase A2 may establish a positive feedback loop, converting acute inflammation into chronic inflammation. Consequently, inhibitors of Cytosolic Phospholipase A2 may prevent inflammation in vivo by interfering with cellular activation and infiltration. We conclude that Cytosolic Phospholipase A2 but not secretory Phospholipase A2 is the predominant enzyme in inflammatory signalling.
Berit Johansen - One of the best experts on this subject based on the ideXlab platform.
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anti vascular effects of the Cytosolic Phospholipase A2 inhibitor avx235 in a patient derived basal like breast cancer model
BMC Cancer, 2016Co-Authors: Hanna Maja Tunset, Astrid Jullumstro Feuerherm, Berit Johansen, Jana Cebulla, Riyas Vettukattil, Heidi Helgesen, Olav Engebraten, Gunhild Mari Maelandsmo, Siver Andreas MoestueAbstract:Background Group IVA Cytosolic Phospholipase A2 (cPLA2α) plays an important role in tumorigenesis and angiogenesis. It is overexpressed in basal-like breast cancer (BLBC), which is aggressive and usually triple-negative, making it unresponsive to current targeted therapies. Here, we evaluated the anti-angiogenic effects of a specific cPLA2α inhibitor, AVX235, in a patient-derived triple-negative BLBC model.
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Inhibition of Group IVA Cytosolic Phospholipase A2 by Thiazolyl Ketones in Vitro, ex Vivo, and in Vivo
Journal of Medicinal Chemistry, 2014Co-Authors: George Kokotos, Edward A. Dennis, Astrid Jullumstro Feuerherm, Violetta Constantinou-kokotou, Efrosini Barbayianni, Ishita Shah, Mari Sæther, Victoria Magrioti, Thuy Thanh Nguyen, Berit JohansenAbstract:Group IVA Cytosolic Phospholipase A2 (GIVA cPLA2) is the rate-limiting provider of pro-inflammatory mediators in many tissues and is thus an attractive target for the development of novel anti-inflammatory agents. In this work, we present the synthesis of new thiazolyl ketones and the study of their activities in vitro, in cells, and in vivo. Within this series of compounds, methyl 2-(2-(4-octylphenoxy)acetyl)thiazole-4-carboxylate (GK470) was found to be the most potent inhibitor of GIVA cPLA2, exhibiting an XI(50) value of 0.011 mole fraction in a mixed micelle assay and an IC50 of 300 nM in a vesicle assay. In a cellular assay using SW982 fibroblast-like synoviocytes, it suppressed the release of arachidonic acid with an IC50 value of 0.6 μM. In a prophylactic collagen-induced arthritis model, it exhibited an anti-inflammatory effect comparable to the reference drug methotrexate, whereas in a therapeutic model, it showed results comparable to those of the reference drug Enbrel. In both models, it signi...
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Cytosolic Phospholipase A2 regulates tnf induced production of joint destructive effectors in synoviocytes
PLOS ONE, 2013Co-Authors: Randi Magnus Sommerfelt, Astrid Jullumstro Feuerherm, Kymry Jones, Berit JohansenAbstract:Introduction Rheumatoid arthritis (RA) is an inflammatory disease of the joint characterized by chronic synovitis causing pain, swelling and loss of function due to destruction of cartilage and bone. The complex series of pathological events occurring in RA is largely regulated via excessive production of pro-inflammatory cytokines, the most prominent being tumor necrosis factor (TNF). The objective of this work was to elucidate possible involvement of group IVA Cytosolic Phospholipase A2 (cPLA2α) in TNF-induced regulation of synovitis and joint destructive effectors in RA, to evaluate the potential of cPLA2α as a future therapeutic target.
Y Hori - One of the best experts on this subject based on the ideXlab platform.
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Cytosolic Phospholipase A2 alpha inhibitor pyrroxyphene displays anti arthritic and anti bone destructive action in a murine arthritis model
Inflammation Research, 2010Co-Authors: K Kuwabara, Mika Kobayashi, Katsutoshi Yamada, K Seno, Yoshinari Gahara, Jun Ishizaki, Y HoriAbstract:Objective The aim of this study is to verify the crucial role of Cytosolic Phospholipase A2 alpha (cPLA2 alpha) in the pathogenesis of collagen-induced arthritis in mice and to determine the anti-arthritic effects of pyrroxyphene, a cPLA2 alpha inhibitor.
George Kokotos - One of the best experts on this subject based on the ideXlab platform.
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Highly Potent 2-Oxoester Inhibitors of Cytosolic Phospholipase A2 (GIVA cPLA2)
ACS omega, 2018Co-Authors: Anastasia Psarra, Maroula G. Kokotou, Gerasimia Galiatsatou, Varnavas D. Mouchlis, Edward A. Dennis, George KokotosAbstract:Cytosolic Phospholipase A2 (GIVA cPLA2) has attracted great interest as a medicinal target because it initiates the eicosanoid cascade and is involved in a number of inflammatory diseases. As a consequence, the development of potent synthetic inhibitors is of great importance. We have developed highly potent 2-oxoester inhibitors of GIVA cPLA2 presenting XI(50) values between 0.000019 and 0.000066. We demonstrate that the 2-oxoester functionality is essential for in vitro inhibitory activity, making these inhibitors useful research reagents. However, their high reactivity results in rapid degradation of the inhibitors in human plasma, limiting their pharmaceutical utility without further modification.
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Inhibition of Group IVA Cytosolic Phospholipase A2 by Thiazolyl Ketones in Vitro, ex Vivo, and in Vivo
Journal of Medicinal Chemistry, 2014Co-Authors: George Kokotos, Edward A. Dennis, Astrid Jullumstro Feuerherm, Violetta Constantinou-kokotou, Efrosini Barbayianni, Ishita Shah, Mari Sæther, Victoria Magrioti, Thuy Thanh Nguyen, Berit JohansenAbstract:Group IVA Cytosolic Phospholipase A2 (GIVA cPLA2) is the rate-limiting provider of pro-inflammatory mediators in many tissues and is thus an attractive target for the development of novel anti-inflammatory agents. In this work, we present the synthesis of new thiazolyl ketones and the study of their activities in vitro, in cells, and in vivo. Within this series of compounds, methyl 2-(2-(4-octylphenoxy)acetyl)thiazole-4-carboxylate (GK470) was found to be the most potent inhibitor of GIVA cPLA2, exhibiting an XI(50) value of 0.011 mole fraction in a mixed micelle assay and an IC50 of 300 nM in a vesicle assay. In a cellular assay using SW982 fibroblast-like synoviocytes, it suppressed the release of arachidonic acid with an IC50 value of 0.6 μM. In a prophylactic collagen-induced arthritis model, it exhibited an anti-inflammatory effect comparable to the reference drug methotrexate, whereas in a therapeutic model, it showed results comparable to those of the reference drug Enbrel. In both models, it signi...
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structure activity relationship of 2 oxoamide inhibition of group iva Cytosolic Phospholipase A2 and group v secreted Phospholipase A2
Journal of Medicinal Chemistry, 2007Co-Authors: Efrosini Barbayianni, Edward A. Dennis, Dimitra Hadjipavloulitina, Daren Stephens, A C Wong, Panagiota Moutevelisminakakis, S F Baker, George KokotosAbstract:The Group IVA Cytosolic Phospholipase A2 (GIVA cPLA2) is a key provider of substrates for the production of eicosanoids and platelet-activating factor. We explored the structure−activity relationship of 2-oxoamide-based compounds and GIVA cPLA2 inhibition. The most potent inhibitors are derived from δ- and γ-amino acid-based 2-oxoamides. The optimal side-chain moiety is a short nonpolar aliphatic chain. All of the newly developed 2-oxoamides as well as those previously described have now been tested with the human Group V secreted PLA2 (GV sPLA2) and the human Group VIA calcium-independent PLA2 (GVIA iPLA2). Only one 2-oxoamide compound had appreciable inhibition of GV sPLA2, and none of the potent GIVA cPLA2 inhibitors inhibited either GV sPLA2 or GVIA iPLA2. Two of these specific GIVA cPLA2 inhibitors were also found to have potent therapeutic effects in animal models of pain and inflammation at dosages well below the control nonsteroidal anti-inflammatory drugs.
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Inhibition of Group IVA Cytosolic Phospholipase A2 by Novel 2-Oxoamides in Vitro, in Cells, and in Vivo
Journal of Medicinal Chemistry, 2004Co-Authors: George Kokotos, Vassilios Loukas, Tim J. D. Smith, Violetta Constantinou-kokotou, Dimitra Hadjipavlou-litina, Stavroula Kotsovolou, Antonia Chiou, Christopher C. Beltzner, Edward A. DennisAbstract:The Group IVA Cytosolic Phospholipase A2 (GIVA PLA2) is a particularly attractive target for drug development because it is the rate-limiting provider of proinflammatory mediators. We previously reported the discovery of novel 2-oxoamides that inhibit GIVA PLA2 [Kokotos, G.; et al. J. Med. Chem. 2002, 45, 2891−2893]. In the present work, we have further explored this class of inhibitors and found that the 2-oxoamide functionality is more potent when it contains a long 2-oxoacyl residue and a free carboxy group. Long-chain 2-oxoamides based on γ-aminobutyric acid and γ-norleucine are potent inhibitors of GIVA PLA2. Such inhibitors act through a fast and reversible mode of inhibition in vitro, are able to block the production of arachidonic acid and prostaglandin E2 in cells, and demonstrate potent in vivo anti-inflammatory and analgesic activity.
