Pharmaceutical Synthesis. Coordinator: Roberti

Design and synthesis of novel bioactive small molecules which can be either lead candidates for the development of new therapeutic agents or useful probes to investigate different pathways and functions of target protein inside the cells (Chemical Biology)

Research themes

The main research topics concern the design and synthesis of small molecules able to modulate molecular target involved in cancer development or cystic fibrosis.The rational design of new molecules is carried out in collaboration with the computational pharmaceutical chemistry group (Prof. Recanatini).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.

Development of RNF5 inhibitors as potential drugs for Cystic Fibrosis basic defect The F508del mutation causes the arrest of the maturation of CFTR protein. Correctors are able to rescue F508del-CFTR, either by act directly on CFTR or by modulating other proteins thus affecting CFTR maturation. A recent studies highlighted the E3 ubiquitin ligase RNF5 as a target whose inhibition leads to mutant CFTR rescue both in vitro and in vivo. Through a computational approach, based on ligand docking and virtual screening, a drug-like small molecule (inh-02) that inhibits RNF5 was identified. Treatment with inh-02 causes significant F508del-CFTR rescue in immortalized and primary bronchial epithelial cells from F508del homozygous CF patients. Our aims are: i) the optimization of RNF5 inhibitors by synthesizing novel analogs; ii) the evaluation of possible individual variability in the efficacy of RNF5 inhibitors; iii) the evaluation of possible toxicity of RNF5 inhibitors; iv) the validation of RNF5 as a drug target for cystic fibrosis and provide evidences to support its druggability.

Lab members

Greta Bagnolini (PhD student) e-mail: greta.bagnolini3@unibo.it

Irene Brusa (PhD student) e-mail: irene.brusa2@unibo.it

Internship projects

Contact Coordinator of research group

Main publications

 Marinella Roberti, Fabrizio Schipani, Greta Bagnolini, Domenico Milano, Elisa Giacomini, Federico Falchi, Andrea Balboni, Marcella Manerba, Fulvia Farabegoli, Francesca De Franco, Janet Robertson, Saverio Minucci, Isabella Pallavicini, Giuseppina Di Stefano, Stefania Girotto, Roberto Pellicciari, and Andrea Cavalli (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, ISSN: 0223-5234, doi: 10.1016/j.ejmech.2019.01.008.

Falchi, Federico, Giacomini, Elisa, Masini, Tiziana, Boutard, Nicolas, Di Ianni, Lorenza, Manerba, Marcella, Farabegoli, Fulvia, Rossini, Lara, Robertson, Janet, Minucci, Saverio, Pallavicini, Isabella, Di Stefano, Giuseppina, Roberti, Marinella, Pellicciari, Roberto, Cavalli, Andrea (2017). Synthetic Lethality Triggered by Combining Olaparib with BRCA2-Rad51 Disruptors. ACS CHEMICAL BIOLOGY, vol. 12, p. 2491-2497, ISSN: 1554-8929, doi: 10.1021/acschembio.7b00707.

 Rupiani S.; Guidotti L.; Manerba M.; Di Ianni L.; Giacomini E.; Falchi F.; Di Stefano G.; Roberti M.; Recanatini M. (2016). Synthesis of natural Urolithin M6, a Galloflavin mimetic as potential inhibitor of Lactate dehydrogenase A. ORGANIC & BIOMOLECULAR CHEMISTRY, vol. 14, p. 10981-10987. DOI: 10.1039/c6ob01977c. 

Pizzirani D., Roberti M., Grimaudo S., Di Cristina A., Pipitone R.M., Tolomeo M., Recanatini M. (2009). Identification of biphenyl-based hybrid molecules able to decrease the intracellular level of Bcl-2 protein in Bcl-2 overexpressing leukemia cells. JOURNAL OF MEDICINAL CHEMISTRY, vol. 52, p. 6936-6940. doi: 10.1021/jm900907s.

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