Our research interests are in Medicinal Inorganic and Bioinorganic Chemistry. Specifically, the study of the role of metal ions in biological systems and of the mechanisms of action of metalbased anticancer agents are active topics of our research program. Besides synthetic inorganic chemistry and structural characterization of new metal complexes, we strongly focus on an intensive biological evaluation of the new compounds as possible therapeutic agents, and on the investigation of their mechanisms of action via the implementation of biophysical and analytical techniques coupled to pharmacological methods. Furthermore, novel applications for metal-based molecules, including supramolecular coordination complexes, are explored in various domains of chemical biology, bioanalytical chemistry and drug delivery.
The main topics include:
- Design and synthesis of coordination and organometallic gold complexes for biological applications: as therapeutic agents and chemical probes.
- Molecular investigations of metal compounds' interactions with biologically active ligands (e.g. proteins, nucleic acids).
- Development of supramolecular assemblies as targeted drug delivery systems.
- Synthesis of photoactivable metal compounds.
- Development of chemical strategies to couple metal compounds to biomolecules.
Among the possible pharmacological targets for cytotoxic gold complexes, zinc finger (ZF) proteins occupy an important place, being involved in a wide range of functions in DNA repairing, recognition, transcription, and replication. These processes are essential for cell growth and development, having direct implications in health and disease. In fact, ZFs are frequently recognized as possible medicinal targets. Our group recently reported on the ability of gold complexes to inhibit selected zinc finger domains via the displacement of Zn2+ from the peptide by gold ions, leading to formation of the so-called ‘‘gold-finger’’ domains.
We have recently identified the aquaporins (AQPs), membrane water and glycerol channels with crucial roles in normal human physiology and pathophysiology, as possible targets for gold compounds. Selective inhibition of AQPs by gold complexes may provide an innovative approach to targeted therapies in different diseases, including cancer, malaria, fibrosis and angiogenesis. Moreover, the use of potent and selective AQPs inhibitors will help unravelling the various roles of these proteins in health and disease.
Metal-mediated self-assemblies of the general formula MxLy (M = metal ion, L = ligand) have emerged as a promising research area of supramolecular chemistry because of their applicability in various fields such as molecular recognition, catalysis and drug delivery. So far, only few studies have been reported on the biological effects of these metal-based chemical entities in cells, and there is still limited proof of their ability to act as drug delivery systems. Therefore, new M2L4 metallacages (M = Pd2+, Pt2+ etc.) are synthesized and tested as drug delivery systems. Moreover, we explore different strategies to tether metallacages to biomolecules, including peptides, as targeting moieties. The assessment of the cages’ stability and toxicity in biological environments proceed in parallel to their chemical design.
A main aim of this project is to tether a drug to targeting moiety (e.g. antibody) via a metal-based linker to guarantee selective drug release at the target site (e.g. cancer cells/tissues). It is essential that the linker does not interfere with the chemical and biological properties of the drug and of the targeting group, respectively.
The rational design of gold compounds as stabilizers of G-quadruplexes (G4s) is attempted with possible applications as anticancer agents. G-quadruplexes are peculiar secondary DNA architectures adopted by guanine-rich nucleic acid sequences, which have shown promise as anticancer drug targets. Our pioneering results in this area have shown that organometallic Au(I) NHCs compounds with caffeine-type ligands can stabilize G4 structures potently and selectively with respect to classical duplex DNA. Thus, the proposed project is aimed at optimizing the design of gold compounds with enhanced G4 stabilizing properties, and increased selectivity.
The use of metal compounds as possible tools to enhance resolution in mass spectrometry imaging techniques is another recent area of interest in our group which includes the synthesis and bio-conjugation of different families of transition metal compounds to peptides/antibodies to implement MSI in complex biological samples (e.g. cancer tissues).