• complexes
• dual ligands
• glioblastoma
• molybdenum

Candidato: Vottero Tommaso
Relatore: Tiziano Marzo
Corso di studi: CTF
SSD: CHIM08
Titolo: New strategies against glioblastoma: Mo2-based complexes bearing anticancer ligands
Glioblastoma is the most common malignant primary brain tumor and it's one of the most
aggressive with only 5,8% 5-year survival rate.
Studies proved that GBM presents resistance in the capacity to avoid apoptosis, the programmed
cell death.
Thus, the use of apoptosis-inductors ligands, such as TSPO ligands or inhibitors of the MDM2/p53
bond, could provide a suitable strategy for new therapies.
Mitochondria play an important role in apoptosis, because they are involved in the mitochondrial
membrane permeability transition (MPT) and the sub-sequential release of pro-apoptotic proteins,
like Cytocrome c.
The channels responsible for MPT are the mitochondrial permeability transition pore (MPTP) and
the channels formed by pro-apoptotic proteins, belonging to the Bcl2 class.
TSPO, or Translocator Protein, is a key component of complex of proteins involved in MPTP and it's
overexpressed in tumor cells.
P53 is a transcription factor who moderates the response of the cell to stress and also can directly
induce the permeabilization of outer mitochondrial membrane while MDM2 is a product of p53
inducted gene and provide a negative feedback control over p53 itself.
Starting from 2014, the research group where this thesis was conducted has developed and later
enhanced, a class of dual inhibitors featuring phenylindolylglyoxyldipeptide structure, active both
on TSPO and MDM2/p53 interaction and capable of blocking the in-vitro proliferation of GBM cells,
with higher potency compared to the single target standards (Nutlin-3 for p53 and PK11195 for
TSPO).
Molybdenum possess low toxicity and it's used for various clinical application, from enhancement
of immunological reactions to treatment of Wilson's disease and cancer.
In chemotherapy, many types of Mo-containing compound are used, both as inorganic and organic
compounds and their activity is supposed to be caused by the ability to incorporate
pharmacological active ligands with the Mo core, which can lead to various effects in cell biology,
such as formation of ROS, peroxidation of lipids, DNA-protein cross-linking and the activation or
the inhibition of cellular pathways.
In this study, two molecules of this class have been chosen for the developing of coordinating
complexes with a bimetallic core made of Molybdenum atoms, due to its anticancer properties and
its ability to form complexes with several compounds, in order to improve the release of the
molecules in the cells and their potency.