AACOCF3 (arachidonyl trifluoromethyl ketone) is a potent inhibitor of cytosolic phospholipase A2 (cPLA2) with an IC50 value of approximately 10μM. By irreversibly alkylating the enzyme's active site, AACOCF3 blocks the release of arachidonic acid and the subsequent production of pro-inflammatory eicosanoids. AACOCF3 is widely used in the study of inflammatory pathways, neuroinflammation, and lipid signaling mechanisms[1]. Because cPLA2 is also involved in the activation of calpain in skeletal muscle, AACOCF3 is also capable of regulating mitochondrial function[2]. Recently, cPLA2 has been closely associated with the development of various cancers, and AACOCF3 has been considered a potential drug for combating cancer development[3, 4].
In vitro, AACOCF3 (5μM) can block the activation of prostaglandins (PGs) by epidermal growth factor (EGF) through the MARK signaling pathway, thereby inhibiting mitosis in corneal epithelial cells[5]. AACOCF3 (1.3–10μM) inhibits the activation of cPLA2 induced by lipopolysaccharide (LPS), reduces the production of reactive oxygen species (ROS) and nitric oxide in microglial cells, and prevents morphological changes associated with the activation of primary microglial cells[6].
In vivo, A treatment regimen of intravenous injection of AACOCF3 (4 mM, 50 μL) at 30 minutes post-injury, followed by daily intraperitoneal injections of AACOCF3 (4 mM, 200 μL), significantly reduced the lesion area in spinal cord injury (SCI) mice and improved the indicators of hind limb locomotor function, as well as improved the balance and coordination abilities[7]. In a rat model of spinal cord injury, intravenous injection of AACOCF3 (7.13mg/kg) significantly increases the number of surviving neurons and oligodendrocytes in the rat model, exerting a neuroprotective effect on rats[8].
References:
[1] 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 Jun 3;269(22):15619-24.
[2] Supinski GS, Alimov AP, Wang L, et al. Calcium-dependent phospholipase A2 modulates infection-induced diaphragm dysfunction. Am J Physiol Lung Cell Mol Physiol. 2016 May 15;310(10):L975-84.
[3] Pan P, Qin G, Wang B, et al. HDAC5 Loss Enhances Phospholipid-Derived Arachidonic Acid Generation and Confers Sensitivity to cPLA2 Inhibition in Pancreatic Cancer. Cancer Res. 2022 Dec 16;82(24):4542-4554.
[4] Li J, Zhang M, Sun Q, et al. CENPF interaction with PLA2G4A promotes glioma growth by modulating mTORC1 and NF-κB pathways. Cancer Cell Int. 2025 Mar 1;25(1):73.
[5] Kang SS, Li T, Xu D, et al. Inhibitory effect of PGE2 on EGF-induced MAP kinase activity and rabbit corneal epithelial proliferation. Invest Ophthalmol Vis Sci. 2000 Jul;41(8):2164-9.
[6] Chuang DY, Simonyi A, Kotzbauer PT, et al. Cytosolic phospholipase A2 plays a crucial role in ROS/NO signaling during microglial activation through the lipoxygenase pathway. J Neuroinflammation. 2015 Oct 31;12:199.
[7] Liu NK, Deng LX, Zhang YP, et al. Cytosolic phospholipase A2 protein as a novel therapeutic target for spinal cord injury. Ann Neurol. 2014 May;75(5):644-58.
[8] Huang W、Bhavsar A、Ward RE, et al. Arachidonyl trifluoromethyl ketone is neuroprotective after spinal cord injury. J Neurotrauma. 2009 Aug;26(8):1429-34.
AACOCF3（花生四烯酰三氟甲基酮）是一种胞质磷脂酶A2（cPLA2）的强效抑制剂，IC50值约为10 μM。AACOCF3通过不可逆烷基化酶活性位点阻断花生四烯酸释放及后续促炎性类二十烷酸生成，被广泛应用于炎症通路、神经炎症及脂质信号机制研究[1]。由于cPLA2还参与骨骼肌钙蛋白酶的激活，因此AACOCF3也被具备调节线粒体的功能[2]。最近，cPLA2被认为与多种癌症的发展密切相关，AACOCF3也被认为潜在的对抗癌症发展的药物[3, 4]。
体外实验中，AACOCF3（5μM）可阻碍表皮生长因子（EGF）通过MARK信号通路激活前列腺素（PGs）抑制角膜上皮细胞的有丝分裂[5]。AACOCF3（1.3-10μM）抑制脂多糖（LPS）诱导cPLA2的激活，降低小胶质细胞中活性氧（ROS）和一氧化氮的产生，抑制原代小胶质细胞的激活[6]。
在体内，按照造模后30min静脉注射AACOCF3 (4 mM，50μL)，随后每天一次腹腔注射AACOCF3 (4 mM，200μL)的治疗方案，可以显著减少了脊髓损伤（SCI）小鼠的病变面积，提高了SCI小鼠的后肢运动功能的指标，以及改善平衡和协调能力[7]。在脊髓损伤大鼠模型中，静脉注射AACOCF3（7.13mg/kg），可增加大鼠模型的存活的神经元和少突胶质细胞的数量显着增加，对大鼠的神经功能起到保护作用[8]。