2-Oxoamide inhibitors of phospholipase A2 activity and cellular arachidonate release based on dipeptides and pseudodipeptides

Barbayianni, Efrosini; Stephens, Daren; Grkovich, Andrej; Magrioti, Victoria; Hsu, Yuan-Hao; Dolatzas, Panagiotis; Kalogiannidis, Dimitrios; Dennis, Edward A.; Kokotos, George

doi:10.1016/j.bmc.2009.03.069

Cited by 18 publications

(29 citation statements)

References 39 publications

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“…Pyrrophenone likely inhibits cPLA 2 ␣ via formation of a hemiketal between its ketone carbonyl and the active site serine of the enzyme based on the ability of polarized ketones to form stable hemiketals with serine proteases and esterases (51)(52)(53). To provide support for this mechanism we tested the effect of pyrrophenone-OH in which the ketone was reduced to the secondary alcohol.…”

Section: Effect Of Pyrrophenone and The Triazole Urea Inhibitor Kt195mentioning

confidence: 99%

Serine Hydrolase Inhibitors Block Necrotic Cell Death by Preventing Calcium Overload of the Mitochondria and Permeability Transition Pore Formation

Yun

Lee

Ghosh

et al. 2014

Journal of Biological Chemistry

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Background: Mitochondrial calcium overload triggers permeability transition pore formation, fatty acid release, and necrotic cell death. Results: Pyrrophenone and KT195 inhibit cell death by blocking mitochondrial calcium uptake. Conclusion: Serine hydrolase inhibitors block mitochondrial calcium uptake but do not directly inhibit the enzyme releasing fatty acids during pore formation. Significance: Serine hydrolase inhibitors have potential to block necrotic cell death associated with disease.

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Section: Effect Of Pyrrophenone and The Triazole Urea Inhibitor Kt195mentioning

confidence: 99%

Serine Hydrolase Inhibitors Block Necrotic Cell Death by Preventing Calcium Overload of the Mitochondria and Permeability Transition Pore Formation

Yun

Lee

Ghosh

et al. 2014

Journal of Biological Chemistry

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“…Methyl arachidonyl fluorophosphonates (MAFP) are also potent GVIA iPLA 2 inhibitors, but they are irreversible, and not specific for iPLA 2 [16]. Another class of GVIA iPLA 2 inhibitors is the 2-oxoamides based on dipeptides and pseudo dipeptides, but they also inhibit cPLA 2 [17]. In 1995, fatty acyl trifluoromethylketones (TFKs) were identified as promising GVIA iPLA 2 inhibitors that target the catalytic Ser [15].…”

Section: Introductionmentioning

confidence: 99%

Computer-aided drug design guided by hydrogen/deuterium exchange mass spectrometry: A powerful combination for the development of potent and selective inhibitors of Group VIA calcium-independent phospholipase A2

Mouchlis

Morisseau

Hammock

et al. 2016

Bioorganic & Medicinal Chemistry

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Potent and selective inhibitors for phospholipases A2 (PLA2) are useful for studying their intracellular functions. PLA2 enzymes liberate arachidonic acid from phospholipids activating eicosanoid pathways that involve cyclooxygenases (COX) and lipoxygenases (LOX) leading to inflammation. Anti-inflammatory drugs target COX and LOX; thus, PLA2 can also be targeted to diminish inflammation. This paper describes the employment of enzymatic assays, hydrogen/deuterium exchange mass spectrometry (DXMS) and computational chemistry to develop PLA2 inhibitors. Beta-thioether trifluoromethylketones (TFKs) were screened against human GVIA calcium-independent, GIVA cytosolic and GV secreted PLA2s. These compounds exhibited inhibition towards Group VIA calcium-independent PLA2 (GVIA iPLA2), with the most potent and selective inhibitor 3 (OTFP) obtaining an XI(50) of 0.0002 mole fraction (IC50 of 110 nM). DXMS binding experiments in the presence of OTFP revealed the peptide regions of GVIA iPLA2 that interact with the inhibitor. Molecular docking and dynamics simulations in the presence of a membrane were guided by the DXMS data in order to identify the binding mode of OTFP. Clustering analysis showed the binding mode of OTFP that occurred 70% during the simulation. The resulted 3D complex was used for docking studies and a structure-activity relationship (SAR) was established. This paper describes a novel multidisciplinary approach in which a 3D complex of GVIA iPLA2 with an inhibitor is reported and validated by experimental data. The SAR showed that the sulfur atom is vital for the potency of beta-thioether analogues, while the hydrophobic chain is important for selectivity. This work constitutes the foundation for further design, synthesis and inhibition studies in order to develop new beta-thioether analogues that are potent and selective for GVIA iPLA2 exclusively.

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“…We have developed a novel class of 2-oxoamides as inhibitors of GIVA cPLA 2 . 25–31 2-Oxoamides were initially designed to target the active site serine of GIVA cPLA 2 . However, it became clear that some 2-oxoamides could also inhibit GVIA iPLA 2 .…”

Section: Resultsmentioning

confidence: 99%

2-Oxoamides based on dipeptides as selective calcium-independent phospholipase A 2 inhibitors

Smyrniotou

Kokotou

Mouchlis

et al. 2017

Bioorganic & Medicinal Chemistry

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Calcium-independent phospholipase A2 (GVIA iPLA2) has recently attracted interest as a medicinal target. The number of known GVIA iPLA2 inhibitors is limited to a handful of synthetic compounds (bromoenol lactone and polyfluoroketones). To expand the chemical diversity, a variety of 2-oxoamides based on dipeptides and ether dipeptides were synthesized and studied for their in vitro inhibitory activity on human GVIA iPLA2 and their selectivity over the other major intracellular GIVA cPLA2 and the secreted GV sPLA2. Structure-activity relationship studies revealed the first 2-oxoamide derivative (GK317), which presents potent inhibition of GVIA iPLA2 (XI(50) value of 0.007) and at the same time significant selectivity over GIVA cPLA2 and GV sPLA2.

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2-Oxoamide inhibitors of phospholipase A2 activity and cellular arachidonate release based on dipeptides and pseudodipeptides

Cited by 18 publications

References 39 publications

Serine Hydrolase Inhibitors Block Necrotic Cell Death by Preventing Calcium Overload of the Mitochondria and Permeability Transition Pore Formation

Serine Hydrolase Inhibitors Block Necrotic Cell Death by Preventing Calcium Overload of the Mitochondria and Permeability Transition Pore Formation

Computer-aided drug design guided by hydrogen/deuterium exchange mass spectrometry: A powerful combination for the development of potent and selective inhibitors of Group VIA calcium-independent phospholipase A2

2-Oxoamides based on dipeptides as selective calcium-independent phospholipase A 2 inhibitors

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