Our research interests are in the field of Medicinal Inorganic and Bioinorganic Chemistry. In particular, the study of the role of metal ions in biological systems and of the mechanisms of action of metal-based (anticancer & antibacterial) agents are active topics of our research program. Besides synthetic inorganic chemistry and structural characterization of novel metal complexes (coordination and organometallics), 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.
Key achievements have been the identification of proteins as important targets for the pharmacological and toxicological activity of metallodrugs. Furthermore, in the area of supramolecular coordination chemistry, we have advanced the study of self-assembled metallacages for biomedical applications, including as drug delivery systems.
Overall, novel applications of metal-based compounds/chemical scaffolds are explored in various domains of chemical biology, bio-analytical chemistry and physiology.
The main topics developed in our lab 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 coordination assemblies as drug delivery systems.
- Synthesis of photoactivable metal compounds.
- Development of chemical strategies to couple metal compounds to biomolecules.
The main research themes are:
Aquaporins: design of gold complexes as selective inhibitors
We have recently identified the aquaporins (AQPs), membrane water and glycerol channels with crucial roles in normal human physiology and pathophysiology, as possible target systems for gold compounds. Selective inhibition of AQPs by gold complexes may provide an innovative approach to targeted therapies in different diseases (e.g. cancer, fibrosis, angiogenesis). Moreover, the use of potent and selective inhibitors will help unravelling the various roles of AQPs in health and disease.
AQP animation video
Self-assembled metallacages as drug delivery systems
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. Thus, new M2L4 metallacages (M = Pd2+, Pt2+, Co2+ etc.) with photophysical properties are synthesized and tested as drug delivery systems. Moreover, we explore different strategies to tether metallacages to biomolecules (such as peptides) as targeting moieties. The assessment of the cages’ stability and toxicity in biological environments proceed in parallel to their chemical design.
Development of metal-based compounds as zinc-finger protein inhibitors
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, replication, apoptosis and metabolism. These processes are essential for cell growth and development, having direct implications in health and disease. Therefore, ZFs are frequently recognized as possible medicinal targets.
Among ZF proteins, PARP-1 is believed to be involved in DNA repair mechanisms, also related to the development of cisplatin resistance in cancer cells. Our group recently reported on the ability of Au complexes to inhibit PARP-1. The hypothesized mechanism of inhibition displacement of Zn2+ from the ZF peptide by gold ions leads to decreased protein activity, and to formation of the so-called ‘‘gold-finger’’ (GF) domain.
N-heterocyclic carbene complexes as G-quadruplex stabilizers
This project includes the design of gold compounds as stabilizers of G-quadruplexes nucleic acid sequences (G4s) with possible applications as anticancer agents. G-quadruplexes are peculiar nucleic acid architectures adopted by guanine-rich DNA and RNA sequences, whose stability originates in the stacking of contiguous G-quartets (a planar and cyclic K+-promoted association of four guanines in a Hoogsteen hydrogen-bonding arrangement). G4s are currently intensively studied, because they are suspected to play important roles in crucial cellular events: quadruplex-forming DNA sequences are indeed found both in eukaryotic telomeres and in promoter regions of identified oncogenes. Interestingly, the formation of quadruplexes causes a net decrease in the activity of the enzyme telomerase, responsible for maintaining the length of telomeres. Therefore, molecules that template the formation or stabilize the structure of G4s might pave the way to the development of new effective anticancer drugs, based on selective telomerase inhibition.
Our pioneering recent results in this area have shown that organometallic Au(I) NHC 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 a more extended family of gold compounds with enhanced G4 stabilizing properties, and increased selectivity.
Metal-based linkers to achieve targeted therapeutic agents
A main aim of this project is to bind drug and targeting moiety (e.g. antibody) robustly together via a metal-based linker to guarantee that the drug remains tightly bound to the conjugate in the bloodstream until selective drug releases at the target site (e.g. cancer cells/tissues). Importantly, the linker should not interfere with the chemical and biological properties of the drug and the targeting group.
Metal compounds to improve Mass Spectrometry Imaging (MSI)
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. tissues).