Discovery of long-chain salicylketoxime derivatives as monoacylglycerol lipase (MAGL) inhibitors.

Bononi, Giulia; Granchi, Carlotta; Lapillo, Margherita; Giannotti, Massimiliano; Nieri, Daniela; Fortunato, Serena; Boustani, Maguie El; Caligiuri, Isabella; Poli, Giulio; Carlson, Kathryn E; Kim, Sung Hoon; Macchia, Marco; Martinelli, Adriano; Rizzolio, Flavio; Chicca, Andrea; Katzenellenbogen, John A; Minutolo, Filippo; Tuccinardi, Tiziano (2018). Discovery of long-chain salicylketoxime derivatives as monoacylglycerol lipase (MAGL) inhibitors. European journal of medicinal chemistry, 157, pp. 817-836. Elsevier Masson SAS 10.1016/j.ejmech.2018.08.038

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Other Institutions > NCCR TransCure
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Chicca, Andrea

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

0223-5234

Publisher:

Elsevier Masson SAS

Language:

English

Submitter:

Barbara Järmann-Bangerter

Date Deposited:

20 Feb 2019 11:28

Last Modified:

20 Feb 2019 11:28

Publisher DOI:

10.1016/j.ejmech.2018.08.038

PubMed ID:

30144699

Uncontrolled Keywords:

Cancer Ketoxime MAGL Monoacylglycerol lipase inhibitors

BORIS DOI:

10.7892/boris.125026

URI:

https://boris.unibe.ch/id/eprint/125026

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