Design Synthesis and in Vitro Evaluation of New Monoacylglycerol Lipase Inhibitors as Anticancer Agents

Abstract

A crucial serine hydrolase enzyme called monoacylglycerol lipase is responsible for newlinehydrolysing monoacylglycerols like 2-arachidonoylglycerol (2-AG) and converting them into newlinefree fatty acids and glycerol. The endocannabinoid system is significantly influenced by newlinemonoacylglycerol lipase (MAGL), which is found in the CNS as well as in nearby organs such newlineas the liver, kidney, testis, lungs, prostate, and small intestine. The endocannabinoid system is newlinefound to be widespread throughout the central and peripheral nervous systems and is crucial in newlinethe regulation of several functions, including memory, the immune system, synaptic plasticity, newlineappetite, reproduction, learning, stress response, sleep, and pain perception. Two membrane- newlinebound G protein-coupled proteins, CB1 and CB2, make up the endocannabinoid system. These newlinereceptors contain the endocannabinoids 2-AG and N-arachidonoylethanolamine (anandamide; newlineAEA). MAGL is a member of the hydrolase superfamily. According to research, fatty acid newlinehydrolase (FAAH) hydrolyses anandamide, whereas MAGL hydrolyses 2-AG primarily to an newlineextent of 85% with a minor contribution from / hydrolase-6 and -12 (ABHD6 and ABHD12), newlinereleasing the pro-inflammatory eicosanoid precursor arachidonic acid (AA) and glycerol. In newlinethe brain, 2-AG is hydrolysed by MAGL to produce 50% of the AA, while cytosolic newlinephospholipase A2 is responsible for producing AA in the peripheral tissues. Consequently, newlineinhibition of the MAGL can result in a rise in 2-AG levels, which activates the endocannabinoid newlineneurotransmission system and causes the brain to exhibit antinociceptive, anxiolytic, newlineantiemetic, anti-inflammatory, and neuroprotective properties. Several aggressive tumours, newlineincluding colorectal cancer, neuroblastoma, and nasopharyngeal carcinoma, have been found newlineto be regulated by the network of free fatty acids (FFA). MAGL is a metabolic key enzyme newlinethat makes it possible for the tumour cells to mobilise and use free fatty acids from the neutral fats that have been stored in the body.