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Digital archive of theses discussed at the University of Pisa

 

Thesis etd-12122022-154117


Thesis type
Tesi di laurea magistrale LM5
Author
BERTINI, FEDERICA
URN
etd-12122022-154117
Thesis title
Synthesis of glycoconjugated benzoylpiperidines as potential reversible MAGL inhibitors
Department
FARMACIA
Course of study
CHIMICA E TECNOLOGIA FARMACEUTICHE
Supervisors
relatore Prof. Minutolo, Filippo
relatore Prof.ssa Granchi, Carlotta
relatore Dott.ssa Bononi, Giulia
Keywords
  • Inhibitors
  • Benzoylpiperidines
  • Glycoconjugation
  • Warburg effect
  • Monoacylglycerol lipase
Graduation session start date
18/01/2023
Availability
Full
Summary
Monoacylglycerol lipase (MAGL) is a cytosolic serine hydrolase that catalyzes the degradation of the major endocannabinoid neurotransmitter, 2-arachidonoylglycerol, implicated in many physiological and pathological processes, such as pain, inflammation, neuroprotection and cancer.
MAGL plays a key role in the development and spread of cancer, as it was found to be upregulated in aggressive cancer cells and primary tumors. MAGL-mediated hydrolysis of monoacylglycerols in peripheral tissue leads to the production of free fatty acids which are used by rapidly growing tumor cells as building blocks for the formation of new cellular membranes and for the synthesis of pro-tumorigenic signaling factors.
Due to the broad-spectrum of its therapeutic implications, MAGL has drawn increasing attention as a promising drug target to develop anti-inflammatory, anti-nociceptive and anti-cancer agents. Despite this, several studies suggested that inhibition of MAGL performed by irreversible MAGL inhibitors results in desensitization of CB1 receptors and ultimately impairs the benefits associated to the indirect CB1 stimulation. Therefore, the identification of reversible MAGL inhibitors represents the basis for the development of an alternative promising therapeutic approach in order to overcome the drawbacks associated with irreversible MAGL inhibitors.
The research group in which I carried out my thesis project discovered the class of benzoylpiperidine-based MAGL inhibitors.
Furthermore, one of the most important hallmarks of cancer cells consists in a metabolic shift, which is also known as the Warburg effect. This effect involves an augmented aerobic glycolysis, and in particular it is characterized by an increased glucose uptake by cancer cells.
Therefore, the aim of my thesis is the development of glycoconjugated benzoylpiperidines that act as reversible MAGL inhibitors and, at the same time, exploit the enhanced sugar uptake of cancer cells. These conjugates were synthesized by the attachment of a glucose moiety to the benzoylpiperidine portion by mean of a 1,2,3-triazole linker.
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