Bononi, Giulia; Di Stefano, Miriana; Poli, Giulio; Ortore, Gabriella; Meier, Philip; Masetto, Francesca; Caligiuri, Isabella; Rizzolio, Flavio; Macchia, Marco; Chicca, Andrea; Avan, Amir; Giovannetti, Elisa; Vagaggini, Chiara; Brai, Annalaura; Dreassi, Elena; Valoti, Massimo; Minutolo, Filippo; Granchi, Carlotta; Gertsch, Jürg and Tuccinardi, Tiziano (2022). Reversible Monoacylglycerol Lipase Inhibitors: Discovery of a New Class of Benzylpiperidine Derivatives. Journal of medicinal chemistry, 65(10), pp. 7118-7140. American Chemical Society 10.1021/acs.jmedchem.1c01806
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Monoacylglycerol lipase (MAGL) is the enzyme responsible for the metabolism of 2-arachidonoylglycerol in the brain and the hydrolysis of peripheral monoacylglycerols. Many studies demonstrated beneficial effects deriving from MAGL inhibition for neurodegenerative diseases, inflammatory pathologies, and cancer. MAGL expression is increased in invasive tumors, furnishing free fatty acids as pro-tumorigenic signals and for tumor cell growth. Here, a new class of benzylpiperidine-based MAGL inhibitors was synthesized, leading to the identification of 13, which showed potent reversible and selective MAGL inhibition. Associated with MAGL overexpression and the prognostic role in pancreatic cancer, derivative 13 showed antiproliferative activity and apoptosis induction, as well as the ability to reduce cell migration in primary pancreatic cancer cultures, and displayed a synergistic interaction with the chemotherapeutic drug gemcitabine. These results suggest that the class of benzylpiperidine-based MAGL inhibitors have potential as a new class of therapeutic agents and MAGL could play a role in pancreatic cancer.
Item Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine |
UniBE Contributor: |
Meier, Philip, Chicca, Andrea, Gertsch, Jürg |
Subjects: |
500 Science > 570 Life sciences; biology 600 Technology > 610 Medicine & health |
ISSN: |
0022-2623 |
Publisher: |
American Chemical Society |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
09 May 2022 08:51 |
Last Modified: |
05 Dec 2022 16:19 |
Publisher DOI: |
10.1021/acs.jmedchem.1c01806 |
PubMed ID: |
35522977 |
BORIS DOI: |
10.48350/169837 |
URI: |
https://boris.unibe.ch/id/eprint/169837 |
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