2. Academic Validation
  3. Discovery of long-chain salicylketoxime derivatives as monoacylglycerol lipase (MAGL) inhibitors

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

  • Eur J Med Chem. 2018 Sep 5:157:817-836. doi: 10.1016/j.ejmech.2018.08.038.
Giulia Bononi 1,  Carlotta Granchi 2,  Margherita Lapillo 1,  Massimiliano Giannotti 1,  Daniela Nieri 3,  Serena Fortunato 1,  Maguie El Boustani 4,  Isabella Caligiuri 5,  Giulio Poli 1,  Kathryn E Carlson 6,  Sung Hoon Kim 6,  Marco Macchia 1,  Adriano Martinelli 1,  Flavio Rizzolio 7,  Andrea Chicca 3,  John A Katzenellenbogen 6,  Filippo Minutolo 1,  Tiziano Tuccinardi 1
Affiliations

Affiliations

  • 1 Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126, Pisa, Italy.
  • 2 Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126, Pisa, Italy. Electronic address: carlotta.granchi@unipi.it.
  • 3 Institute of Biochemistry and Molecular Medicine, NCCR TransCure, University of Bern, CH-3012, Bern, Switzerland.
  • 4 Pathology Unit, Department of Molecular Biology and Translational Research, National Cancer Institute and Center for Molecular Biomedicine, Aviano (PN), Italy; Doctoral School in Molecular Biomedicine, University of Trieste, 34100, Trieste, Italy.
  • 5 Pathology Unit, Department of Molecular Biology and Translational Research, National Cancer Institute and Center for Molecular Biomedicine, Aviano (PN), Italy.
  • 6 Department of Chemistry, University of Illinois at Urbana-Champaign, 600 S. Mathews Avenue, Urbana, IL, 61801, USA.
  • 7 Pathology Unit, Department of Molecular Biology and Translational Research, National Cancer Institute and Center for Molecular Biomedicine, Aviano (PN), Italy; Department of Molecular Sciences and Nanosystems, Ca' Foscari University, Venezia, 30123, Italy.
PMID: 30144699 DOI: 10.1016/j.ejmech.2018.08.038
Abstract

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.

Keywords

Cancer; Ketoxime; MAGL; Monoacylglycerol lipase inhibitors.

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