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Digital archive of theses discussed at the University of Pisa

 

Thesis etd-05302022-143735


Thesis type
Tesi di dottorato di ricerca
Author
BONONI, GIULIA
URN
etd-05302022-143735
Thesis title
Development of therapeutic and diagnostic agents targeting tumor lipid and sugar metabolism
Academic discipline
CHIM/08
Course of study
SCIENZA DEL FARMACO E DELLE SOSTANZE BIOATTIVE
Supervisors
tutor Prof. Minutolo, Filippo
tutor Prof.ssa Granchi, Carlotta
Keywords
  • anti-cancer agents
  • cancer cell metabolism
  • cancer imaging
  • cancer therapy
  • glycoconjugated metal complexes
  • glycolytic metabolism
  • monoacylglycerol lipase (MAGL)
  • PROteolysis Targeting Chimera (PROTAC)
  • Warburg effect
Graduation session start date
09/06/2022
Availability
Withheld
Release date
09/06/2025
Summary
Cancer cells are characterized by an uncontrolled and rapid proliferation due to defects in the regulatory system that controls cells’ growth and division. This unbridled proliferation of cancer cells requires a big amount of nutrients and energy that consequently causes changes and adaptations in their metabolic profile. Indeed, the metabolic reprogramming is necessary to satisfy the rapid growth of the tumor and to allow its survival in adverse conditions. Dysregulation in carbohydrate, aminoacid (especially glutamine) and lipid metabolism are the main characteristics of cancer cells alterations.
Therefore, the aim of my PhD Thesis was the development of therapeutic and diagnostic agents able to interfere with tumor lipid and sugar metabolism. For what concerns the reprogrammed lipid metabolism, I focused on one key enzyme: monoacylglycerol lipase (MAGL), which is involved in cancer progression, invasiveness and aggressiveness. Especially, I aimed to design and synthesize small organic molecules able to reversibly inhibit MAGL with potential anti-cancer activity. Another aim of this Thesis was the development of the first PROteolysis Targeting Chimera (PROTAC) small molecules targeting MAGL (anti-MAGL PROTACs) able to induce enzyme ubiquitination followed by its degradation. Regarding altered glucose metabolism, the last goal of this this Thesis was to develop glycoconjugated metal complexes as diagnostic probes for the selective IR visualization of glycolytic cancer cells by exploiting the well-characterized metabolic switch of tumors called Warburg effect.
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