Dipartimento di Scienza e Tecnologia del Farmaco

Descrizione del progetto

Membri:
Silvano Cadamuro   (Dipartimento di Chimica)
Annamaria Deagostino    (Dipartimento di Chimica)
Eliano Diana    (Dipartimento di Chimica)
Elena Maria Ghibaudi    (Dipartimento di Chimica)
Enzo Laurenti    (Dipartimento di Chimica)
Domenica Marabello    (Dipartimento di Chimica)

Partners:
Department of Chemistry, University of Turin 

Description

Platinum-based drugs are among the most active anticancer agents and are successfully used in a wide variety of human malignancies. However, their use is greatly limited by severe side effects and by the onset of acquired and/or intrinsic resistance. For these reasons, the development of novel antitumor metallodrugs with an improved pharmacological profile is currently a major goal of medicinal chemistry and drug design. Several vanadium(IV) compounds have shown a wide spectrum of antitumor properties, thus offering an appealing alternative for cancer chemotherapy. To date, the exact mechanism of action for these compounds has not been determined and the targets are largely unknown. This project aims at gaining knowledge on the mechanism of action of selected vanadyl and vanadocene compounds at the cellular and molecular levels and to develop new vanadium compounds, based on the structural modulation of the existing ones, which will be able to recognise specific biological targets. New V(IV) compounds will be synthesized and labelled with fluorescent probes in order to follow their fate inside cells by confocal microscopy. Further, conjugation with different kinds of vectors (proteins and small organic molecules) will allow directing them towards specific target sites.

Mass spectrometry and Electron Spin Resonance analyses will allow to characterize their adducts with isolated targets. Molecular modelling will help in designing new V(IV) complexes with improved reactivity and selectivity profiles, in order to maximize their uptake by specific cell lines. The anticancer activity of new and existing compounds will be assessed on human cell cultures and tissues through biochemical assays, to evaluate the effect on cell proliferation, cell cycle and apoptosis. The synthesis of new fluorescent and cell-specific V(IV) complexes and the understanding of their mechanism of action at the cellular and molecular levels will be the expected results of this project.

Keywords:
Anticancer compounds, Metallo-drugs, Vanadyl Complexes