2. Academic Validation
  3. Design, synthesis and biological evaluation of second-generation benzoylpiperidine derivatives as reversible monoacylglycerol lipase (MAGL) inhibitors

Design, synthesis and biological evaluation of second-generation benzoylpiperidine derivatives as reversible monoacylglycerol lipase (MAGL) inhibitors

  • Eur J Med Chem. 2021 Jan 1:209:112857. doi: 10.1016/j.ejmech.2020.112857.
Carlotta Granchi 1,  Giulia Bononi 1,  Rebecca Ferrisi 1,  Eleonora Gori 1,  Giulia Mantini 2,  Sandra Glasmacher 3,  Giulio Poli 1,  Stefano Palazzolo 4,  Isabella Caligiuri 4,  Flavio Rizzolio 5,  Vincenzo Canzonieri 6,  Tiziana Perin 4,  Jürg Gertsch 3,  Andrea Sodi 7,  Elisa Giovannetti 2,  Marco Macchia 1,  Filippo Minutolo 1,  Tiziano Tuccinardi 8,  Andrea Chicca 3
Affiliations

Affiliations

  • 1 Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126, Pisa, Italy.
  • 2 Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, DeBoelelaan 1117, 1081HV, Amsterdam, the Netherlands; Cancer Pharmacology Lab, Fondazione Pisana per La Scienza, Via Giovannini 13, 56017, San Giuliano Terme, Pisa, Italy.
  • 3 Institute of Biochemistry and Molecular Medicine, NCCR TransCure, University of Bern, CH-3012, Bern, Switzerland.
  • 4 Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081, Aviano, Italy.
  • 5 Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081, Aviano, Italy; Department of Molecular Sciences and Nanosystems, Ca' Foscari University, 30123, Venezia, Italy.
  • 6 Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081, Aviano, Italy; Department of Medical, Surgical and Health Sciences, Università Degli Studi di Trieste, Strada di Fiume 447, Trieste, Italy.
  • 7 Department of Neurosciences, Psychology, Drug Research and Child Health Eye Clinic, University of Florence, AOU Careggi, 50139, Florence, Italy.
  • 8 Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126, Pisa, Italy. Electronic address: tiziano.tuccinardi@unipi.it.
PMID: 33045662 DOI: 10.1016/j.ejmech.2020.112857
Abstract

An interesting Enzyme of the endocannabinoid system is monoacylglycerol Lipase (MAGL). This Enzyme, which metabolizes the endocannabinoid 2-arachidonoylglycerol (2-AG), has attracted great interest due to its involvement in several physiological and pathological processes, such as Cancer progression. Experimental evidences highlighted some drawbacks associated with the use of irreversible MAGL inhibitors in vivo, therefore the research field concerning reversible inhibitors is rapidly growing. In the present manuscript, the class of benzoylpiperidine-based MAGL inhibitors was further expanded and optimized. Enzymatic assays identified some compounds in the low nanomolar range and steered molecular dynamics simulations predicted the dissociation itinerary of one of the best compounds from the Enzyme, confirming the observed structure-activity relationship. Biological evaluation, including assays in intact U937 cells and competitive activity-based protein profiling experiments in mouse brain membranes, confirmed the selectivity of the selected compounds for MAGL versus other components of the endocannabinoid system. An antiproliferative ability in a panel of Cancer cell lines highlighted their potential as potential Anticancer agents. Future studies on the potential use of these compounds in the clinical setting are also supported by the inhibition of cell growth observed both in Cancer organoids derived from high grade serous ovarian Cancer patients and in pancreatic ductal adenocarcinoma primary cells, which showed genetic and histological features very similar to the primary tumors.

Keywords

Benzoylpiperidine derivatives; MAGL; Monoacylglycerol lipase inhibitors.

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