TY - JOUR
T1 - Discovery of long-chain salicylketoxime derivatives as monoacylglycerol lipase (MAGL) inhibitors
AU - Bononi, Giulia
AU - Granchi, Carlotta
AU - Lapillo, Margherita
AU - Giannotti, Massimiliano
AU - Nieri, Daniela
AU - Fortunato, Serena
AU - Boustani, Maguie El
AU - Caligiuri, Isabella
AU - Poli, Giulio
AU - Carlson, Kathryn E.
AU - Kim, Sung Hoon
AU - Macchia, Marco
AU - Martinelli, Adriano
AU - Rizzolio, Flavio
AU - Chicca, Andrea
AU - Katzenellenbogen, John A.
AU - Minutolo, Filippo
AU - Tuccinardi, Tiziano
PY - 2018/9/5
Y1 - 2018/9/5
N2 - 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.
AB - 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.
KW - Cancer
KW - Ketoxime
KW - MAGL
KW - Monoacylglycerol lipase inhibitors
UR - http://www.scopus.com/inward/record.url?scp=85051834719&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85051834719&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2018.08.038
DO - 10.1016/j.ejmech.2018.08.038
M3 - Article
C2 - 30144699
AN - SCOPUS:85051834719
VL - 157
SP - 817
EP - 836
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
ER -