AACOCF3

Inhibitor of cPLA2/anandamide hydrolysis/FAAH CAS# 149301-79-1

AACOCF3

Catalog No. BCC7075----Order now to get a substantial discount!

Product Name & Size Price Stock
AACOCF3:25mg $374.00 In stock
AACOCF3:50mg $636.00 In stock
AACOCF3:125mg $1496.00 In stock
AACOCF3:250mg $2618.00 In stock
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Chemical structure

AACOCF3

3D structure

Chemical Properties of AACOCF3

Cas No. 149301-79-1 SDF Download SDF
PubChem ID 5280436 Appearance Powder
Formula C21H31F3O M.Wt 356.47
Type of Compound N/A Storage Desiccate at -20°C
Synonyms Arachidonyl trifluoromethyl ketone
Solubility Soluble in ethanol (supplied pre-dissolved in anhydrous ethanol, 5mg/ml)
Chemical Name (6Z,9Z,12Z,15Z)-1,1,1-trifluorohenicosa-6,9,12,15-tetraen-2-one
SMILES CCCCCC=CCC=CCC=CCC=CCCCC(=O)C(F)(F)F
Standard InChIKey PLWROONZUDKYKG-DOFZRALJSA-N
Standard InChI InChI=1S/C21H31F3O/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-16-17-18-19-20(25)21(22,23)24/h6-7,9-10,12-13,15-16H,2-5,8,11,14,17-19H2,1H3/b7-6-,10-9-,13-12-,16-15-
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of AACOCF3

DescriptionInhibitor of cytosolic (85 kDa) phospholipase A2. Also inhibits fatty acid amide hydrolase (FAAH, anandamide amidase) in vitro.

AACOCF3 Dilution Calculator

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AACOCF3 Molarity Calculator

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Preparing Stock Solutions of AACOCF3

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.8053 mL 14.0264 mL 28.0529 mL 56.1057 mL 70.1321 mL
5 mM 0.5611 mL 2.8053 mL 5.6106 mL 11.2211 mL 14.0264 mL
10 mM 0.2805 mL 1.4026 mL 2.8053 mL 5.6106 mL 7.0132 mL
50 mM 0.0561 mL 0.2805 mL 0.5611 mL 1.1221 mL 1.4026 mL
100 mM 0.0281 mL 0.1403 mL 0.2805 mL 0.5611 mL 0.7013 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on AACOCF3

AACOCF3 is a potent and selective inhibitor of cytosolic phospholipase A2 with IC50 value of 15 μM [1].

Phospholipase A2 is an enzyme that releases fatty acids from glycerol. Cytosolic phospholipase A2 (cPLA2) plays an important role in inflammation by inducing the release of arachidonic acid from membrane phospholipids.

AACOCF3 is a potent and selective inhibitor of the 85-kDa cPLA2. AACOCF3 inhibited macrophage PLA2 with IC50 value of 15 μM in a concentration-dependent way [1]. AACOCF3 inhibited the release of arachidonic acid (AA) with IC50 values of 2 and 8 μM in platelets and calcium ionophore-challenged U 937 cells, respectively. Also, AACOCF3 inhibited the production of thromboxane B and 12-hydroxyeicosatetraenoic acid (12-HETE), the major metabolites of AA in a dose-dependent way. These results suggested that cPLA2 played a critical role in the generation of AA and 12-HETE [2].

In mice, AACOCF3 inhibited chronic inflammatory responses and inhibited phorbol 12-myristate

13-acetate (PMA)-induced chronic ear edema. In ovalbumin-challenged BALB/c mice, AACOCF3 (20mg/kg) inhibited airway hyper-responsiveness and reduced cellular recruitment in the airway inflammation and airway lumen [3].

References:
[1].  Ackermann EJ, Conde-Frieboes K, Dennis EA. Inhibition of macrophage Ca(2+)-independent phospholipase A2 by bromoenol lactone and trifluoromethyl ketones. J Biol Chem, 1995, 270(1): 445-450.
[2].  Riendeau D, Guay J, Weech PK, et al. Arachidonyl trifluoromethyl ketone, a potent inhibitor of 85-kDa phospholipase A2, blocks production of arachidonate and 12-hydroxyeicosatetraenoic acid by calcium ionophore-challenged platelets. J Biol Chem, 1994, 269(22): 15619-15624.
[3].  Malaviya R, Ansell J, Hall L, et al. Targeting cytosolic phospholipase A2 by arachidonyl trifluoromethyl ketone prevents chronic inflammation in mice. Eur J Pharmacol, 2006, 539(3): 195-204.

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References on AACOCF3

A specific inhibitor of cytosolic phospholipase A2 activity, AACOCF3, inhibits glucose-induced insulin secretion from isolated rat islets.[Pubmed:8561771]

Biochem Biophys Res Commun. 1996 Jan 17;218(2):423-7.

In pancreatic beta-cells, arachidonic acid accumulation results primarily from phospholipid hydrolysis by phospholipase A2, and activation of this enzyme has been shown to accompany glucose-induced insulin secretion. Inhibitors of phospholipase A2 attenuate the secretory response, although the compounds used to date have not discriminated between cytosolic and secretory isoforms of phospholipase A2. In this work, the specific cytosolic phospholipase A2 inhibitor, AACOCF3, caused a dose-dependent inhibition of glucose-induced insulin secretion from isolated rat islets and this response was significantly relieved by exogenous arachidonic acid. The results suggest that, despite the low levels of expression of cytosolic phospholipase A2 in rat islets, this enzyme contributes to the control of glucose-induced insulin secretion in rat pancreatic beta-cells.

The inhibitor of phospholipase-A2, AACOCF3, stimulates steroid secretion by dispersed human and rat adrenocortical cells.[Pubmed:10227584]

Life Sci. 1999;64(15):1287-94.

AACOF3 is a trifluomethylketone analog of arachidonic acid, which inhibits phospholipase-A2 (PLA2). AACOCF3 was found to concentration-dependently increase basal aldosterone and corticosterone secretion by dispersed rat zona glomerulosa and zona fasciculata/reticularis cells, respectively, as well as aldosterone and cortisol production by dispersed human adrenocortical cells. Maximal effective concentration was 10(-5) M, and elicited about 2.5-3.0-fold rises in steroid output. 10(-5) M AACOCF3 also enhanced submaximally (10(-15)/10(-12) M), but not maximally (10(-9) M) ACTH-stimulated hormonal secretion. Quantitative HPLC showed that 10(-5) M AACOCF3 evokes similar increases (from 2.0- to 3.0-fold) in the basal release of the entire spectrum of adrenocortical steroids (i.e. both intermediate and definitive products of steroid synthesis), thereby suggesting that AACOCF3 acts on the early steps of steroid synthesis. Accordingly, when pregnenolone metabolism is prevented by cyanoketone, 10(-5) M AACOCF3 increased by about 8-10-fold the production of this steroid. In conclusion, we have demonstrated a side-effect of AACOCF3, which may become relevant in studies where this chemical is used to inhibit PLA2 in tissues able to convert cholesterol to pregnenolone.

Inhibition of calcium-independent phospholipase A2 prevents inflammatory mediator production in pulmonary microvascular endothelium.[Pubmed:19059366]

Respir Physiol Neurobiol. 2009 Feb 28;165(2-3):167-74.

Inhalation of allergens can result in mast cell degranulation and release of granule contents, including tryptase, in the lung. Injury to human pulmonary microvascular endothelial cells (HMVEC-L) can also result in activation of the coagulation cascade and thrombin generation. We hypothesize that these proteases activate calcium-independent phospholipase A2 (iPLA2), in HMVEC-L, leading to the production of membrane phospholipids-derived inflammatory mediators. Both thrombin and tryptase stimulation of HMVEC-L increased iPLA2 activity that was inhibited by pretreatment with the iPLA2 selective inhibitor bromoenol lactone (BEL). Arachidonic acid and prostaglandin I2 (PGI2) release were also increased in tryptase and thrombin stimulated cells and inhibited by BEL pretreatment. Pretreating the endothelial cells with AACOCF3 a cytosolic PLA2 inhibitor did not inhibit tryptase or thrombin induced arachidonic acid and PGI2 release. In addition thrombin and tryptase also increased HMVEC-L platelet activating factor (PAF) production that significantly contributes to the recruitment and initial adherence of polymorphonuclear neutrophils (PMN) to the endothelium. Tryptase or thrombin stimulated increase in PMN adherence to the endothelium was inhibited by pretreatment of HMVEC-L with BEL or pretreatment of PMN with CV3988, a PAF receptor specific antagonist. Collectively, these data support our hypothesis that iPLA2 activity is responsible for membrane phospholipid hydrolysis in response to tryptase or thrombin stimulation in HMVEC-L. Therefore selective inhibition of iPLA2 may be a pharmacological target to inhibit the early inflammation in pulmonary vasculature that occurs as a consequence of mast cell degranulation or acute lung injury.

Inhibitors of arachidonoyl ethanolamide hydrolysis.[Pubmed:8083191]

J Biol Chem. 1994 Sep 16;269(37):22937-40.

Arachidonoyl ethanolamide (anandamide) is a naturally occurring brain constituent that binds to a specific brain cannabinoid receptor (CBR1). An amidase activity (anandamide amidase) in membrane fractions of brain and in cultured neuroblastoma cells rapidly degrades anandamide to arachidonic acid (Deutsch, D. G., and Chin, S. (1993) Biochem. Pharmacol. 46, 791-796). In the current study, analogs of anandamide representing three classes of putative transition-state inhibitor (trifluoromethyl ketones, alpha-keto esters, and alpha-keto amides) were synthesized and tested as inhibitors of anandamide hydrolysis in vitro and as ligands for CBR1. The trifluoromethyl ketones and alpha-keto esters showed nearly 100% inhibition of anandamide hydrolysis in vitro at 7.5 microM inhibitor and 27.7 microM anandamide. Arachidonyl trifluoromethyl ketone was the only synthetic compound in the series of fatty acid derivatives able to displace [3H]CP-55940 binding to CBR1 with a Ki of 0.65 microM. It was also the most effective inhibitor in intact neuroblastoma cells, leading to a 12-fold increase of cellular anandamide levels at 12 microM. From the action of these inhibitors on this hydrolytic enzyme, it seems likely that anandamide is cleaved by a mechanism that involves an active-site serine hydroxyl group. These inhibitors may serve as useful tools to elucidate the role anandamide plays in vivo.

Arachidonyl trifluoromethyl ketone, a potent inhibitor of 85-kDa phospholipase A2, blocks production of arachidonate and 12-hydroxyeicosatetraenoic acid by calcium ionophore-challenged platelets.[Pubmed:8195210]

J Biol Chem. 1994 Jun 3;269(22):15619-24.

Arachidonyl trifluoromethyl ketone (AACOCF3) is a potent and selective slow binding inhibitor of the 85-kDa cytosolic phospholipase A2 (cPLA2) (Street, I. P., Lin, H.-K., Laliberte, F., Ghomashchi, F., Wang, Z., Perrier, H., Tremblay, N. M., Huang, Z., Weech, P. K., and Gelb, M. H. (1993) Biochemistry 32, 5935-5940). AACOCF3 and a number of its structural analogues have been used to investigate the role of cPLA2 in the cellular generation of free arachidonic acid (AA) and in eicosanoid biosynthesis. AACOCF3 inhibited the release of AA from calcium ionophore-challenged U937 cells (IC50 = 8 microM, 2 x 10(6) cells ml-1) and from platelets (IC50 = 2 microM, 4 x 10(7) cells ml-1). Arachidonyl methyl ketone (AACOCH3) and AACH(OH)CF3, both of which are noninhibitory to the purified cPLA2, did not inhibit the production of AA in the ionophore-challenged cells. In addition to the release of AA, AACOCF3 also inhibited the production of 12-hydroxyeicosatetraenoic acid (12-HETE) and thromboxane B2, two of the major metabolites of AA produced by platelets. The inhibition of 12-HETE biosynthesis showed a dose dependence similar to that of AA release in ionophore-challenged platelets; however, when platelet 12-HETE production was stimulated with 10 microM AA to circumvent the PLA2-dependent step, AACOCF3 no longer inhibited the production of 12-HETE. In contrast, AACOCF3 blocked thromboxane B2 formation by both calcium ionophore- and AA-challenged platelets, indicating that the compound affects the cyclooxygenase pathway in addition to AA release. The crude cytosol and membrane fractions from platelets were assayed for calcium-dependent and calcium-independent PLA2 activities and for the susceptibility of each to inhibition by AACOCF3. At AACOCF3 concentrations as high as 10 mol %, only one of the observed PLA2 activities was inhibited by more than 25%. The AACOCF3-susceptible PLA2 (77% inhibition at 1.6 mol %) was found in the cytosolic platelet fraction and showed the functional characteristics of the cPLA2. These results suggest that the cPLA2 plays an important role in the generation of free AA for 12-HETE biosynthesis in platelets.

Description

Phospholipase A2 inhibitor

Keywords:

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