Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126, Pisa, Italy.
Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126, Pisa, Italy.
Eur J Med Chem. 2018 Sep 5;157:817-836. doi: 10.1016/j.ejmech.2018.08.038. Epub 2018 Aug 16.
Monoacylglycerol lipase (MAGL) is the enzyme hydrolyzing the endocannabinoid 2-arachidonoylglycerol (2-AG) to free arachidonic acid and glycerol. Therefore, MAGL is implicated in many physiological processes involving the regulation of the endocannabinoid system and eicosanoid network. MAGL inhibition represents a potential therapeutic target for many diseases, including cancer. Nowadays, most MAGL inhibitors inhibit this enzyme by an irreversible mechanism of action, potentially leading to unwanted side effects from chronic treatment. Herein, we report the discovery of long-chain salicylketoxime derivatives as potent and reversible MAGL inhibitors. The compounds herein described are characterized by a good target selectivity for MAGL and by antiproliferative activities against a series of cancer cell lines. Finally, modeling studies suggest a reasonable hypothetical binding mode for this class of compounds.
单酰基甘油脂肪酶（MAGL）是水解内源性大麻素 2-花生四烯酸甘油（2-AG）为游离花生四烯酸和甘油的酶。因此，MAGL 参与许多涉及内源性大麻素系统和类二十烷酸网络调节的生理过程。MAGL 抑制代表了许多疾病（包括癌症）的潜在治疗靶点。目前，大多数 MAGL 抑制剂通过不可逆的作用机制抑制这种酶，这可能导致慢性治疗产生不必要的副作用。在此，我们报告了长链水杨酰基肟衍生物作为强效和可逆的 MAGL 抑制剂的发现。本文所述的化合物具有良好的 MAGL 靶选择性和对一系列癌细胞系的抗增殖活性。最后，模型研究表明，该类化合物具有合理的假设结合模式。
