Organic synthetic compounds

Our goal is the investigation of novel chemical structures to establish the interaction with cellular macromolecules, i.e. nucleic acids or proteins, by means of spectroscopic and electrophoretic methods. The effects on the tridimensional structure of nucleic acids and the ability to interfere with the catalytic activity of enzymes, involved in process strictly related with cell proliferation, are studied in depth. Lisa Dalla Via

Natural compounds

The aim of the project is the identification of novel natural compounds with potential antitumor activity. Thanks to the collaboration with Mexican research groups, we evaluate the anticancer effect of secondary metabolites isolated from plants used in traditional medicine. The molecular targets responsible of the biological activity are studied and the involvement of different intracellular signaling pathways is investigated on human tumor cells. Lisa Dalla Via

Metal-based complexes

We study new metal-based anticancer complexes with a special emphasis on their interaction with particular receptors and protein targets associated with tumor malignancy. The binding, the cell uptake and the interactions are studied in depth on resistant cells. Cutting-edge technological approaches are employed for the study of drug-target(s) interactions. Lisa Dalla Via

Self-assembling nanoparticles

The need to face the resistance of different kind of tumor cells, move our interest to study new self-assembled nanoparticles obtained by using anticancer drug conjugates.
We evaluate the antitumor effect of novel self-assembling nanoparticles on human tumor cell lines resistant to conventional anticancer drugs and the molecular targets involved in the mechanisms modulating the drug resistance are investigated. Lisa Dalla Via

Metal Complexes

The Group aims to develop the use of metal-containing compounds as chemotherapeutic agents. As a result, this research is highly interdisciplinary, at the interface of medicinal chemistry, biology and medicine.  While the anticancer activity of platinum containing compounds has been the subject of intensive research worldwide, the medicinal properties of other metals have been relatively little explored. We have been involved in the research of novel Group 10 and 11 metal complexes, in particular copper (I,II) complexes, for which a plethora of studies highlighted an high potential as antitumor agents able to circumvent platinum medication drawbacks. We focus on an intensive biological evaluation of the new compounds and on the investigation of their mechanisms of action via the application of analytical techniques coupled to pharmacological methods. The information about structure and activity we get from these studies will allow us to develop new drugs that are not only active in the treatment of many different types of cancer, but which are also very selective and have less side-effects for the patient. Our research allow us to individuate a specific group of copper(I) complexes with promising activity against a number of different types of solid cancers. We are studying their interaction with biomolecules such as DNA and proteins, which are potential targets. 
Valentina Gandin e Cristina Marzano 

NC inhibitors

Our aim is to design and investigate the mechanism of action of novel synthetic ligands targeting specific nucleic acid sequences and/or structural contexts in DNA/RNA chains, in particular those relevant for antiviral therapeutic treatment (TAR RNA, cTAR, SL 1-4 of the HIV genome).  Searching for compounds able to interfere with the activity of the HIV-1 nucleocapsid (NC) protein, we characterize the physico-chemical parameters of DNA/RNA recognition by established or potential drugs, aimed at the exploration of the Structure-Activity Relationship (SAR) and the elucidation of their putative mechanism of action. Barbara Gatto Alice Sosic

DNA alkylating agents

In collaboration with research groups in Germany and US, we are exploring ideas aimed at the discovery of new chemotherapies whose features were simplicity in synthesis, possible ample decoration of the molecular structure, and an intended mechanism of action whose therapeutic viability had been well established by clinical practices. By simplifying the structure of a complex natural compound with antineoplastic activity, we obtained, through relatively simple synthetic processes, a wide library of bis-chloropiperidines that we verified through various analytical techniques to be DNA alkylators. Our international group is developing the most promising molecules of this class as new chemotherapeutics in the cancer therapy field, analyzing thoroughly their cytotoxicity and pharmacological profile in cancer cells and enhancing their selectivity with the use of intelligent nanotechnology systems. Barbara Gatto Alice Sosic

 Mass spectrometry-based approaches in drug development

Mass spectrometry has become a key technology to investigate macromolecular complexes. We employ electrospray ionization mass spectrometry (ESI-MS) to elucidate protein-nucleic acids-ligand interactions in order to obtain valuable insight into the molecular mechanism of action of promising therapeutic agents (antiviral and anticancer agents). We elucidate binding details for different classes of chemical entities, differing in their mode of interaction with the target. In particular, we are exploring compounds acting as DNA and/or RNA cross-linking agents, as well as small molecules able to interact with nucleic acids in a non-covalent manner. The employment of MS as a biophysical tool in drug development allows us 1) to unambiguously elucidate at the molecular level the reactions of small molecules with proteins and/or nucleic acid targets, and 2) to investigate nucleic acids structures, structure-function relationships of nucleic acids-ligands and nucleic acids-protein complexes involved in essential biological processes. Moreover, in collaboration with research groups in Czech Republic and US, we apply ion mobility mass spectrometry (IM-MS) to reveal the dynamics of protein­ RNA interactions.  Barbara Gatto Alice Sosic

Profiling of nucleic acid foldings

Selective targeting of nucleic acids

Targeting of nucleic acids by small molecules is a strategy that finds applications in therapy (anticancer, antibacterial and aniviral drugs) as well as in diagnostic. The macromolecules-ligand interaction is a multicomponent process but it is possible to study it along each single step. This approach provides a comprehensive overview of the structural requirements of the ligand thus improving rational ligands design and optimization. Currently ongoing projects in this field cover: Protein-DNA recognition; G-quadruplex ligands; Synthetic nucleases; Biosensors. Claudia Sissi

Topoisomerases poisons

Topoisomerases are key enzymes which are required for the proper progression of cell cycles in eukaryotic and prokaryotic cells. A validate mechanism of action for efficient anticancer and antibacterial agents is represented by the induction of a DNA damage trough the impairment of their normal activity. Worth of note, this can occur at different stage of the enzyme catalytic cycle. Along the years we acquired a valuable knowhow on the study of these mechanism and now, with the recent advances on the structural characterization of these proteins we are using it to further optimize their targeting by new selective and potent small molecules. Claudia Sissi