Medicinal Chemistry-Chemical Biology. Coordinator: Roberti

Design and synthesis of novel biologically active small molecules, which can be used as putative lead candidates or tools for the discovery of new therapeutically relevant targets

Research themes

The main research topics concern the design and synthesis of small molecules able to modulate molecular target involved in cancer development. The rational design of new molecules is carried out in collaboration with the computational pharmaceutical chemistry group (Prof. M. Recanatini and Prof. M. Masetti). The synthetic strategies applied include, in addition to "classical" methods, a combinatorial chemistry approach, working in parallel to obtain small libraries of drug-like molecules that are characterized by spectroscopic and spectrometric techniques. In addition, microwave-assisted synthesis is carried out according to a sustainable chemistry. Particular attention is given to synthetic methodologies that allow for quick and efficient collection of complex natural compounds such as multicomponent reactions including domino sequences with particular attention to those stereochemically controlled by the use of catalysts. In the following the two main projects are described.

Design and synthesis of disruptors of Rad51/BRCA2 interaction
Rad51/BRCA2 interaction plays a key role on the repair of DNA double strand breaks. The inhibition of this interaction makes cancer cells more sensitive to DNA damaging agents and to inhibitors of DNA repair (e.g. PARP inhibitors). The new identified disruptors can be studied in association as chemosensitizer to develop anticancer therapies and to trigger a fully small molecules induced synthetic lethality (Fig.1, A-B).

Green synthesis of compounds of pharmaceutical interest supported by artificial intelligence
In this project, undertaken in the current year as part of a PON project concerning the GREEN thematic area, statistical methodology and computational modelling will be exploited for the design of green chemical reactions, capable of providing molecules of pharmaceutical interest with a low environmental impact and reduced costs. Through a combined approach, algorithms will be described that identify possible green reactions within the network of all known reactions and subsequently it will be demonstrated that the predicted sequences can be performed experimentally, with a reduction in the number of experiments and the environmental impact. In particular, we investigate GSK-3𝛽, a constitutively active and ubiquitously expressed serine/threonine protein kinase. GSK-3𝛽 is a promising target for the development of an effective disease modifying treatment in Alzheimer’s disease (AD).

Lab Members

Marinella Roberti, Associate Professor (e-mail)

Laura Poppi, PhD student - Biological studies (e-mail

Giovanni Ferrandi, PhD student- Synthesis of small molecules (e-mail)

Dominga Evangelista, PhD student - Computational modeling and design ( e-mail)  

Internship projects

Contact Coordinator of research group

Main publications

  • Bagnolini,G., Balboni,B., Schipani, F., Gioia,D., Veronesi,M., De Franco,F,. Kaya,C., Jumde,R.P., Ortega,J.A., Girotto,S., Hirsch,A.K.H., Roberti,M., Cavalli, A.(2022). Identification of RAD51-BRCA2 Inhibitors UsingN-Acylhydrazone-Based Dynamic Combinatorial Chemistry. ACS Med Chem Lett.Vol. 13, 1262-1269, doi: 10.1021/acsmedchemlett.2c00063
  • Schipani,F,. Manerba,M., Marotta,R., Poppi,L., Gennari,A., Rinaldi,F., Armirotti,A., Farabegoli,F., Roberti,M., Di Stefano,G., Rocchia,W., Girotto,S., Tirelli,N., Andrea, C. (2022). The Mechanistic Understanding of RAD51 Defibrillation: A Critical Step in BRCA2-Mediated DNA Repair by Homologous Recombination. Vol. 23, 8338.
  • Mazzei,L., Contaldo,U., Musiani,F., Cianci,M., Bagnolini,G., Roberti,M., Stefano Ciurli, S.(2021). Inhibition of urease, a Ni-enzyme: the reactivity of a key thiol with mono-and di-substituted catechols elucidated by kinetic, structural and theoretical studies. ANGEW CHEM INT ED ENGL. vol. 60, p. 6029-6035, doi: 10.1002/anie.202014706
  • Bagnolini G., Milano D., Manerba M., Schipani F., Ortega J. A., Gioia D., Falchi F., Balboni A., Farabegoli F., De Franco F., Robertson J., Pellicciari R., Pallavicini I., Peri S., Minucci S., Girotto S., Di Stefano G., Roberti M., Cavalli A. (2020). Synthetic Lethality in Pancreatic Cancer: Discovery of a New RAD51-BRCA2 Small Molecule Disruptor That Inhibits Homologous Recombination and Synergizes with Olaparib. JOURNAL OF MEDICINAL CHEMISTRY, vol. 63, p. 2588-2619, doi: 10.1021/acs.jmedchem.9b01526
  • Roberti,M., Schipani,F., Bagnolini,G., Milano,D., Giacomini,E., Falchi,F., Balboni,A., Manerba,M., Farabegoli,F., De Franco,F., Robertson,J., Minucci,S., Pallavicini,I., Di Stefano,G., Girotto,S., Pellicciari,R., and Cavalli, A.(2019). Rad51/Brca2 Disruptors Inhibit Homologous Recombination and Synergize with Olaparib in Pancreatic Cancer Cells. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 165, p. 80-92, doi: 10.1016/j.ejmech.2019.01.008