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Digital archive of theses discussed at the University of Pisa


Thesis etd-05052020-173629

Thesis type
Tesi di laurea magistrale LM5
Thesis title
Synthesis of new fructose mimetic glycoconjugate-Ruthenium complexes as potential antitumor agents
Course of study
relatore Prof.ssa Di Bussolo, Valeria
relatore Dott. Di Pietro, Sebastiano
relatore Dott.ssa Iacopini, Dalila
  • carbon-carbon cross coupling
  • fructose
  • glycoconjugates
  • Ruthenium complexes
  • sugar transporters (GLUTs)
  • carbohydrate-based triphenylphosphine ligands
  • carbohydrate mimetics
Graduation session start date
Release date
In recent years, fructose dietary consumption has registered a dramatic increase and has been correlated with a parallel rise of the rate of obesity and metabolic syndromes. This led to investigate on fructose involvement in a variety of diseases, including cancer.
Carbohydrates uptake in the mammalian cell is guaranteed by two classes of hexose transporters: active sodium-coupled glucose transporters (SGLTs) and passive glucose transporter proteins (GLUTs). GLUTs belong to the larger major facilitator superfamily (MFS) and facilitate the diffusion of monosaccharides or polyols across the cell membrane down a concentration gradient. So far, 14 isoforms have been identified by genome sequencing and divided into three phylogenetically distinct groups. The members of these classes exhibit a remarkably diverse substrate specificity. In particular, fructose uptake is thought to be mainly mediated by facilitative membrane transporters GLUT2 and 5, the latter being fructose-specific.
Alteration of cellular energy metabolism and consequent overexpression of GLUT transporters, to support tumor sustained growth, represent one of the hallmarks of cancer. This specificity, known as the Warburg effect, represents a potential target for therapeutic intervention.
Indeed, recent studies correlate altered GLUT5 expression with several human diseases and strongly suggest fructose role in the genesis and growth of some types of cancer.
In this perspective, there has been an increasing interest for the synthesis of new fructose glycoconjugates or mimetics for both diagnostic and therapeutic aims. In fact, some of these compounds might actually show a higher affinity for GLUT5 binding site, thus inhibiting fructose cellular uptake.
An interesting alternative approach to inhibition of hexose transporters is to target their overexpression in tumor cells for site-specific delivery of chemotherapeutic agents. This method implies conjugation of a compound showing antitumor activity with a carbohydrate or a glycomimetic that can be recognized by the transporter protein, allowing the glycoconjugate to be internalized as a whole. In this way, the pharmaceutically active core exerts its activity directly inside the cancer cell, exploiting a “Trojan Horse” mechanism.
Recently, in our laboratory new glycoconjugate-Ruthenium complexes have been synthesized, with the idea of combining Ruthenium antitumor activity with glycoconjugates selectivity towards cancer cells. In vitro anticancer activity of these complexes has been evaluated on several tumor cell lines, showing that some of these molecules possess a good cellular uptake and an interesting cytotoxicity on ovarian endometrioid adenocarcinoma cells. Importantly, they did not show activity on healthy cells.
Focusing on fructose mimetics, the main purpose of this thesis project was to design and realize the synthesis of new fructose based-triphenylphosphine ligands, in both furanosic and pyranosic forms, that could be subsequently used to obtain Ruthenium complexes. These glycoconjugated compounds have a triphenylphosphine functionality, which is essential for metal coordination, that is connected to the fructose analogues through an amide bond. Protection of phosphine with borane is necessary to prevent its oxidation, that leads to useless products.
In addition, a typical glycosyl donor such as the trichloroacetimidate (TCA) was investigated for the synthesis of new triphenylphosphine ligands with the glucose moiety connected to the phosphine unit, that coordinates the Ruthenium, by an alkynyl linker.