ETD

Archivio digitale delle tesi discusse presso l'Università di Pisa

Tesi etd-02112011-111054


Tipo di tesi
Tesi di dottorato di ricerca
Autore
GRANCHI, CARLOTTA
URN
etd-02112011-111054
Titolo
New agents against hypoxic tumours counteracting invasiveness and metabolism
Settore scientifico disciplinare
CHIM/08
Corso di studi
SCIENZA DEL FARMACO E DELLE SOSTANZE BIOATTIVE
Relatori
tutor Prof. Minutolo, Filippo
Parole chiave
  • tumour hypoxia
  • pro-drugs
  • N-hydroxyindole
  • metastasis
  • lysyl oxidase
  • lactate dehydrogenase
  • glycolysis
  • Warburg effect
Data inizio appello
22/03/2011
Consultabilità
Completa
Riassunto
My research activity concerns the design and the synthesis of heterocycles which are intended to act against tumour hypoxia. Unlike healthy cells, which are regularly vascularized, cancer tissues are often characterized by hypoxic regions, due to the rapid and uncontrolled cellular growth and the irregular vascular network. This condition brings to the overexpression of several proteins and, among them, two important novel antitumoural targets, that are lysyl oxidase (LOX) and lactate dehydrogenase A (LDH-A), constituted the main focuses of my research, because they are key enzymes involved in hypoxic tumour growth and invasiveness.
In particular, LOX is an enzyme implicated in the remodeling of the extracellular matrix and in the promotion of the metastatic process, so it is deeply involved in the invasive ability of hypoxic tumours. This PhD thesis was aimed to design and synthesize hypoxia-activated nitroaromatic pro-drugs of beta-aminoproprionitrile (BAPN), which is a well-known LOX inhibitor that cannot be developed as a drug due to its many unwanted side effects. These prodrugs should be able to selectively delivery BAPN to hypoxic tumour sites in order to block LOX-induced promotion of invasiveness, reducing systemic side effects. The synthesized molecules were biologically evaluated in LOX inhibition and cell invasion assays, and some compounds proved to be promising LOX inhibitors.
As for LDH-A, this enzyme is involved in the peculiar sugar metabolism that occurs in invasive cancers, consisting in a metabolic switch (called the “Warburg effect”) from oxidative phosphorylation to an increased anaerobic glycolysis. LDH-A constitutes a major checkpoint in the switch from aerobic to anaerobic glycolysis, by catalysing the reduction of pyruvate to lactate. The genetic or chemical inhibition of this enzyme proved to counteract tumour growth. Furthermore, LDH-A is also a safe target, causing myoglobinuria only during intense anaerobic exercise in people with an hereditary deficiency of this enzyme. In this PhD project, a new class of LDH-A inhibitors based on COOH-substituted N-hydroxyindole structure (NHIs) was designed and synthesized. Enzymatic assays and cellular-based experiments led to the discovery of new promising and selective inhibitors of LDH-A.
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