This dissertation describes the research carried out as part of a PhD program in Chemistry from the 1st October 2017 until 30th November 2020. The PhD project investigated the development of inhibitors of enzymes involved in important metabolic pathways, with the final aim to produce an antiproliferative effect. The present thesis combines the works performed at the University of Milan and Vrije Universiteit of Amsterdam. Part A describes the research performed in Amsterdam, NL during my period abroad from January to September 2019 in the research group of Professor Rob Leurs, at the Division of Medicinal Chemistry of the Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit of Amsterdam. In particular, this part outlines the design, synthesis and pharmacological evaluation of two novel series of potent antitrypanosomal agents, identified through SAR exploration and scaffold hopping approach starting from cyclic nucleotide Trypanosoma brucei phosphodiesterase (PDE) inhibitors. PDE enzymes provide a fine control on several biochemical pathways and have recently been demonstrated to be essential for parasite proliferation. Their disruption by RNA interference (RNAi) dramatically increase intracellular cAMP and, consequently, causes complete mortal trypanosome cell lysis. Part B describes the research done at the Department of Pharmaceutical Sciences, University of Milan, under the supervision of Professor Paola Conti, on the design and synthesis of novel covalent inhibitors targeting the glycolytic enzyme Glyceraldehyde-3- phosphate dehydrogenase (GAPDH). Due to its pivotal role in the glycolysis, GAPDH represents a rate-limiting enzyme in those cells that mostly, or exclusively rely on this pathway for energy production. In this context, GAPDH inhibition represents a valuable approach for the development of anticancer and antiparasitic drugs. Due to the presence of a druggable nucleophilic cysteine residue in the catalytic pocket of the target, I focused my attention on the development of covalent GAPDH inhibitors, presenting an electrophilic warhead with a finely tuned reactivity. In particular, Section B2 reportsthe work conducted on the development of Plasmodium falciparum GAPDH inhibitors and the in vitro antiplasmodial activity. Section B3 shows the work performed on the design and synthesis of human GAPDH inhibitors, with in vitro antitumor activity.

DESIGN AND SYNTHESIS OF NOVEL ENZYME INHIBITORS AS ANTIPROLIFERATIVE COMPOUNDS WITH ANTIPROTOZOAL AND ANTICANCER ACTIVITY / A. Galbiati ; supervisor: P. Conti. - : . Dipartimento di Scienze Farmaceutiche, 2021 Mar 18. ((33. ciclo, Anno Accademico 2020. [10.13130/galbiati-andrea_phd2021-03-18].

DESIGN AND SYNTHESIS OF NOVEL ENZYME INHIBITORS AS ANTIPROLIFERATIVE COMPOUNDS WITH ANTIPROTOZOAL AND ANTICANCER ACTIVITY

A. Galbiati
2021

Abstract

This dissertation describes the research carried out as part of a PhD program in Chemistry from the 1st October 2017 until 30th November 2020. The PhD project investigated the development of inhibitors of enzymes involved in important metabolic pathways, with the final aim to produce an antiproliferative effect. The present thesis combines the works performed at the University of Milan and Vrije Universiteit of Amsterdam. Part A describes the research performed in Amsterdam, NL during my period abroad from January to September 2019 in the research group of Professor Rob Leurs, at the Division of Medicinal Chemistry of the Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit of Amsterdam. In particular, this part outlines the design, synthesis and pharmacological evaluation of two novel series of potent antitrypanosomal agents, identified through SAR exploration and scaffold hopping approach starting from cyclic nucleotide Trypanosoma brucei phosphodiesterase (PDE) inhibitors. PDE enzymes provide a fine control on several biochemical pathways and have recently been demonstrated to be essential for parasite proliferation. Their disruption by RNA interference (RNAi) dramatically increase intracellular cAMP and, consequently, causes complete mortal trypanosome cell lysis. Part B describes the research done at the Department of Pharmaceutical Sciences, University of Milan, under the supervision of Professor Paola Conti, on the design and synthesis of novel covalent inhibitors targeting the glycolytic enzyme Glyceraldehyde-3- phosphate dehydrogenase (GAPDH). Due to its pivotal role in the glycolysis, GAPDH represents a rate-limiting enzyme in those cells that mostly, or exclusively rely on this pathway for energy production. In this context, GAPDH inhibition represents a valuable approach for the development of anticancer and antiparasitic drugs. Due to the presence of a druggable nucleophilic cysteine residue in the catalytic pocket of the target, I focused my attention on the development of covalent GAPDH inhibitors, presenting an electrophilic warhead with a finely tuned reactivity. In particular, Section B2 reportsthe work conducted on the development of Plasmodium falciparum GAPDH inhibitors and the in vitro antiplasmodial activity. Section B3 shows the work performed on the design and synthesis of human GAPDH inhibitors, with in vitro antitumor activity.
CONTI, PAOLA
CONTI, PAOLA
enzyme inhibitors; covalent; antiparasitic; antiprotozoal; anticancer; GAPDH; PDE; Trypanosoma brucei; Plasmodium falciparum; scaffold hopping;
Settore CHIM/06 - Chimica Organica
DESIGN AND SYNTHESIS OF NOVEL ENZYME INHIBITORS AS ANTIPROLIFERATIVE COMPOUNDS WITH ANTIPROTOZOAL AND ANTICANCER ACTIVITY / A. Galbiati ; supervisor: P. Conti. - : . Dipartimento di Scienze Farmaceutiche, 2021 Mar 18. ((33. ciclo, Anno Accademico 2020. [10.13130/galbiati-andrea_phd2021-03-18].
Doctoral Thesis
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Descrizione: PhD Thesis Andrea Galbiati R11939
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/827428
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