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Ruolo
Docenti di ruolo di Ia fascia
Qualifica (ricerca)
Professori Ordinari
 
Area Ministeriale
AREA MIN. 03 - Scienze chimiche
Macro-settore concorsuale
03/C - ORGANICO,INDUSTRIALE
Settore SSD
Settore CHIM/06 - Chimica Organica

Fabio Benedetti Fabio Benedetti was born in Trieste on 16 February 1954. He is currently Professor of Organic Chemistry at the Department of Chemical and Pharmaceutical Sciences, University of Trieste. Education 1978: degree in chemistry from the University of Trieste Professional Experience 1978-1979: postgraduate scholarship - Institute of Chemistry, University of Trieste 1979-1982: postdoctoral fellow - University College of North Wales, Bangor (UK) 1982-1983: lectureship - Faculty of Pharmacy, University of Trieste 1983-1992: assistant professor of Organic Chemistry - Faculty of Science, University of Trieste 1992-2005: associate professor of Organic Chemistry 2005-present: professor of Organic Chemistry Visiting Scientist / Professor 1985: University College of North Wales (UK) 1991: Scripps Research Institute, La Jolla (California) Institutional activities and academic appointments 1991-1997: member of the research committee - responsible for the EU liaison office of the University of Trieste in Bruxelles. 1993-2006: member of the Ph.D. School in Chemical Sciences 1995-2000: director of CISAI (Interuniversity Consortium for the Development of International Activities, Brussels) 2003-2006: vice rector for Research 2006-2013: member of the Doctoral School in Chemical and Pharmaceutical Sciences and Technologies 2008-2010: head of the Department of Chemistry 2009-2013: vice rector for Research 2013: vice rector - University of Trieste 2013 to date: head of the College “Luciano Fonda” of the University of Trieste 2013 to date: coordinator of the Open Access committee Teaching (a.a. 2017/2018) - Organic Chemistry 1 - BSc, Chemistry - Bioorganic Chemistry - MSc, Chemistry - "From Enzyme Models to Artificial Enzymes" - PhD degree in Chemistry, University of Trieste and University of Venice Membership in Scientific Societies - Member of the Italian Chemical Society - Member of the American Chemical Society Current Research Interests - the development of new methodologies for the synthesis of dipeptide isosters; - the design, synthesis and evaluation of protease inhibitors active against cancer, viral and neurodegenerative disease; - the study of natural products from coffee; - the design and synthesis of peptides for small molecule recognition. Professor Benedetti has been responsible of research projects funded by the University of Trieste, the Friuli Venezia Giulia Region, by MURST (PRIN and FIRB), CNR (Biotechnology PF), the EU and several companies with which he collaborates actively. Project Coordination (Main Collaborative Projects) PRIN 2003: Stereoselective Approaches to the Synthesis of Isosters of the Glycosylation Site of the CSF114 (Glc)Glycopeptide - Group Leader 2005: Synthesis and Evaluation of HIV-Protease Inhibitors Based on Proline Isosers and Peptidomimetic Epoxides - Group Leader 2008: Synthesis and Evaluation of Peptidomimetic Inhibitors of Viral Proteases and Prolipeptidases - Group Leader 2010: Design and Stereoselective Synthesis of Compounds Active Towards Protein Targets Involved in Viral and Tumor Pathologies - Group Leader FIRB 2001: Synthesis of Modified Peptides for Innovative Therapies Modulating the Immune and Antiviral Response - Group Leader EU 1993: Science: Mass Spectrometry of Adamantyl Glycopeptides. - Group Leader 1998: Marie Curie Training Network: Catalysis of Sequence Selective Amide and Peptide Hydrolysis by Antibodies and Proteins (COSSAC) - Group Leader 2002: Erasmus Intensive Program: Synthesis for Solving Biological Problems - Group Leader 2009: Researchers' Night - Coordinator 2010: Researchers' Night - Coordinator 2011: Researchers' Night - Coordinator Friuli-Venezia Giulia REGION 2000: Development of an Immunoenzymatic Assay for the Monitoring of HIV-PR Inhibitors in Clinical Use for the Treatment of AIDS - Coordinator 2003: Project "R³A² - Regional Network for the Research of Anti-Infective Agents" - Group Leader 2005: Peptidomimetic Inhibitors of Retroviral Proteases and Their Use as Antiviral - Coordinator 2006: New Catalytic Methods for The Industrial Production of Bioactive Molecules - Local Coordinator 2007: Highly Sensitive Kits and Biosensors for the Determination of Algal Toxins in Water and in Fish Products of Friuli Venezia Giulia (SENSTOX) - Group Leader 2016: Technological Applications of New Antineoplastic Agents (Atena) - Group Leader MAIN SCIENTIFIC ACHIEVEMENTS 1) Intramolecular Reactions Research on the ring closure of ω-substituted carbanions has allowed to establish a general reactivity order as a function of ring size for the closure of small to medium size rings. The closure of three membered rings is often the fastest process in intramolecular SN2 reactions thanks to the favourable activation entropy. The closure of five-and six-membered rings is enthalpically favourable, but entropically disfavoured in comparison to three-membered rings. Four-membered rings are not favoured enthalpically nor entropically and their formation is, in general, slower with respect to both three-membered and larger rings. Cyclization of ω-epoxy carbanions is a useful synthetic method for the preparation of 3 to 7-membered cyclic alcohols, combining high stereoselectivity in the epoxidation step and high regioselectivity in the attack of the nucleophile on the epoxide. 2) Dipeptide isosters and peptidomimetic HIV-protease inhibitors The chemistry of epoxyalcohols offers an attractive entry to the synthesis of hydroxyethylene and dihydroxyethylene dipeptide isosters with complete control on the configuration of 3 and 4 stereocenters, respectively. A variety of HIV-PR inhibitors with nM activities can been synthesized with this approach including inhibitors containing a proline isostere which are obtained with an intramolecular variant of the reaction. A new class of inhibitors has been discovered, containing an epoxyalcohol group that, surprisingly, does not react with the catalytic aspartates or other nucleophiles. 3) Catalytic antibodies The sulfonamide group is shown to be an excellent mimic of the transition state for amide hydrolysis. Antibodies obtained against sulfonamides catalyze the hydrolysis of the corresponding amides with accelerations up to 1000-10000 fold. The sulfonamide elicits the formation of an oxyanion hole, stabilizing the transition state by electrostatic interactions and hydrogen bonds, while an aspartate residue provides general base catalysis. This mechanism is unprecedented in biological hydrolysis of amides. 4) Isopeptidase (deubiquitinase) inhibitors and cancer The ubiquitin-proteasome system (UPS) is the main cellular system for the selective degradation of damaged, modified, or misfolded proteins. Cancer cells are highly dependent on the correct functioning of this system, and this has made the UPS an attractive target for the development of selective anticancer drugs. Protein degradation by the UPS takes place in three steps: - Ubiquitination, whereby the target protein is tagged with ubiquitin allowing the protein to be recognized by the proteasome. - Deubiquitination. In order for the protein to enter the proteasome and be processed, the ubiquitin or polyubiquitin tag must be removed by enzymes (deubiquitinases, DUBs, isopeptidases) acting selectively on the isopetide linkage. Six families of DUBs are known, five of which are cysteine-dependent displaying a mechanism analogous to that of cysteine proteases. - Proteolysis, which is carried out by the proteasome’s own proteolytic activity. Concern over side effects and development of resistance to approved proteasome inhibitors, such as bortezomib and caflizomib, has raised interest in targeting upstream enzymes and DUBs in particular. Our work shows that Michael acceptors based on the bis-benzylidenecyclohexanone scaffold are powerful isopeptidase inhibitors possessing good (μM) in vitro and in vivo activity and low toxicity.

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