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

Granchi, Carlotta; Bononi, Giulia; Ferrisi, Rebecca; Gori, Eleonora; Mantini, Giulia; Glasmacher, Sandra; Poli, Giulio; Palazzolo, Stefano; Caligiuri, Isabella; Rizzolio, Flavio; Canzonieri, Vincenzo; Perin, Tiziana; Gertsch, Jürg; Sodi, Andrea; Giovannetti, Elisa; Macchia, Marco; Minutolo, Filippo; Tuccinardi, Tiziano; Chicca, Andrea (2021). Design, synthesis and biological evaluation of second-generation benzoylpiperidine derivatives as reversible monoacylglycerol lipase (MAGL) inhibitors. European journal of medicinal chemistry, 209, p. 112857. Elsevier 10.1016/j.ejmech.2020.112857

[img] Text
1-s2.0-S0223523420308291-main.pdf - Published Version
Restricted to registered users only
Available under License Publisher holds Copyright.

Download (4MB) | Request a copy

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.

Item Type:

Journal Article (Original Article)

Division/Institute:

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

UniBE Contributor:

Glasmacher, Sandra Patricia; Gertsch, Jürg and Chicca, Andrea

Subjects:

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

ISSN:

1768-3254

Publisher:

Elsevier

Language:

English

Submitter:

Barbara Järmann-Bangerter

Date Deposited:

13 Jan 2021 16:46

Last Modified:

17 Jan 2021 02:55

Publisher DOI:

10.1016/j.ejmech.2020.112857

PubMed ID:

33045662

Uncontrolled Keywords:

Benzoylpiperidine derivatives MAGL Monoacylglycerol lipase inhibitors

BORIS DOI:

10.48350/150885

URI:

https://boris.unibe.ch/id/eprint/150885

Actions (login required)

Edit item Edit item
Provide Feedback