Organic Chemistry for Pharmaceutical and Diagnostic Applications Laboratory

Macroarea: Medicinal Chemistry

ERC Sectors: PE5_17 Organic chemistry; PE5_18 Medicinal chemistry; PE5_6 New materials: oxides, alloys, composite, organic-inorganic hybrid, nanoparticles; PE5_15 Polymer chemistry; PE11_9 Nanomaterials engineering, e.g. nanoparticles, nanoporous materials, 1D & 2D nanomaterials; LS6_10 Vaccine development; LS7_3 Nanomedicine.

Research Team

Lab Managers: Ersilia De Lorenzi (Full Professor), Marco Terreni (Full Professor), Massimo Serra (technician)

Junior Staff: Giovanni Bisbano (PhD student), Cecilia Contardi (PhD student), Davide Rubes (PhD student)

Research Line

1. SYNTHESIS OF cRGD DERIVATIVES FOR THE DEVELOPMENT OF THERAPEUTIC NANOSYSTEMS.

Cyclic pentapeptides carrying the Arg-Gly-Asp sequence (cRGD) are well known potent αvβ3 and αvβ5 integrin antagonists. We find new ways to efficiently synthesize novel cRGD-based bioconjugates that may find application for targeted drug delivery systems, as theranostic agents or for cancer cell labelling. Recently we focused our attention on the use of cRGD derivatives to actively target nanosystems (e.g., nanoparticles) directly to the malignant tumor cells.

2. SYNTHESIS OF MOLECULARLY IMPRINTED NANOPARTICLES.

Molecularly Imprinted polymers (MIPs), mainly in the format of nanoparticles, are designed in-house to detect and sense previously inaccessible tumor markers or to discover novel disease biomarkers. The polymerization process is performed in the presence of various templates, among which the tumor-specific glycopeptide derivatives. MIPs are characterized during their design and development for final material optimization and reproducibility.

3. SYNTHESIS OF TUMOR-ASSOCIATED GLYCOPEPTIDES ANTIGENS AS TEMPLATES FOR MIPs.

Synthesis of simplified versions of tumor-specific MUC1 glycopeptides carrying STn antigen. Starting from commercially available pentapeptide epitope we developed an efficient glycosylation protocol which allowed the decoration of starting peptides with various model sugar moieties such as 6’‐sialyllactose (6SL) or 3’-sialyllactose (3SL). The obtained glycopeptides, mimicking the native targets, will find applications as templates for the preparation of MIPs for the specific recognition of cancer biomarkers.

4. DEVELOPMENT OF GLYCOCONJUGATED VACCINES.

This research project aims the development of “dual acting” semi-synthetic glycoconjugate vaccines obtained by combining immunogenic or antigenic oligosaccharides with antigenic proteins from pathogens. The objective is the development of efficient glycosylated vaccine rationally designed from well-defined antigens of relevant pathogens such as Mycobacterium Tuberculosis (MTB). Specifically, the combination of antigenic proteins from MTB with oligosaccharides mimetic of Arabinomannane (the main sugar antigen of MTB) is under investigation In addition, the chemical glycosylation of MTB proteins with oligosaccharides targeting the mannose receptors (MR) of antigen presenting cells (APCs) will be performed to improve the antigen up-take.

5. ASYMMETRIC SYNTHESIS OF QUATERNARY AMINO ACIDS.

Development of asymmetric one-pot protocols for the conversion of racemic α-amino acids into quaternary amino acids endowed with a vinyl/allyl/ethynyl group at the quaternary stereocenter. The incorporation of quaternary amino acids carrying a double/triple bond moiety at Cα not only allows the attainment of biologically active cyclic and stapled peptides, but also would make it possible to explore new routes beyond traditional peptide design such as site-selective peptide modifications, the preparation of multifunctional peptides, cell penetrating peptides and peptide-drug/polymer conjugates.

Publications
  • Ambrosini, S. et al: GLUCURONIDE DIRECTED MOLECULARLY IMPRINTED SOLID-PHASE EXTRACTION: ISOLATION OF TESTOSTERONE GLUCURONIDE FROM ITS PARENT DRUG IN URINE (2012) Analyst, 137(1), pp. 249-254
  • Ambrosini, S. et al: SYNTHESIS AND CHROMATOGRAPHIC EVALUATION OF MOLECULARLY IMPRINTED POLYMERS PREPARED BY THE SUBSTRUCTURE APPROACH FOR THE CLASS-SELECTIVE RECOGNITION OF GLUCURONIDES (2011) Journal of Chromatography A, 1218(39), pp. 6961-696
  • Emgenbroich, M. et al: A PHOSPHOTYROSINE-IMPRINTED POLYMER RECEPTOR FOR THE RECOGNITION OF TYROSINE PHOSPHORYLATED PEPTIDES (2008) Chemistry - A European Journal, 14(31), pp. 9516-9529
  • Filice, M et al; REGIOSELECTIVE MONODEPROTECTION OF PERACETYLATED CARBOHYDRATES (2012) Nature protocols 10; 1783-1796
  • Zheng, C. et al; DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NEW GANGLIOSIDE GM3 ANALOGUES AS POTENTIAL AGENTS FOR CANCER THERAPY (2020) European Journal of Medicinal Chemistry, 189, 112065
  • Hoos, P. et al; HIGHLY EFFICIENT AND SUSTAINABLE SYNTHESIS OF NEOGLYCOPROTEINS USING GALACTOSIDASES (2020) ACS Sustainable Chem. Eng, 8, 6282–6292
  • Li Z., et al; CHEMOENZYMATIC SYNTHESIS OF ARABINOMANNAN (AM) GLYCOCONJUGATES AS POTENTIAL VACCINES FOR TUBERCULOSIS. (2020) European Journal of Medicinal Chemistry, vol. 204, 112578
  • Serra, M. et al; SYNTHESIS OF FUNCTIONALIZED 6,5- AND 7,5-AZABICYCLOALKANE AMINO ACIDS BY METATHESIS REACTIONS (2019) Journal of Organic Chemistry, 84, 15726–15734.
  • Bari, E., Serra, M. et al SILK FIBROIN NANOPARTICLE FUNCTIONALIZATION WITH ARG-GLY-ASP CYCLOPENTAPEPTIDE PROMOTES ACTIVE TARGETING FOR TUMOR SITE-SPECIFIC DELIVERY (2021) Cancers, 13 (5), art. no. 1185, pp. 1-16.
  • Serra, M. et al. SYNTHESIS OF VARIOUSLY FUNCTIONALIZED AZABICYCLOALKANE SCAFFOLDS BY DOMINO METATHESIS REACTIONS (2017) Journal of Organic Chemistry, 82 (20), pp. 11091-11101.
Collaborations

National Collaboration

Academic Institutions

Bice Conti, Rossella Dorati, Department of Drug Sciences, University of Pavia
Maddalena Patrini, Department of Physics, University of Pavia
Pollegioni Loredano, Dipartimento di Biotecnologie e Scienze della Vita, Università degli studi dell’Insubria (Varese)
Paola Conti, Dipartimento di Scienze Farmaceutiche, Università degli studi di Milano Maurizio Mattei Dipartimento di Biologia della Università di Roma Tor Vergata
Marina Torre, Mayra Paolillo, Sergio Schinelli, Department of Drug Sciences, University of Pavia
Filippo Doria, Stefano Protti, Department of Chemistry, University of Pavia
Massimo Carraro, Department of Chemistry and Pharmacy, University of Sassari
Laura Belvisi, Department of Chemistry, University of Milan;

Industries

Dipharma Francis Srl, Baranzate, MI
Farmabios SpA, Gropello Cairoli, PV
ICE SpA, Basaluzzo, AL

 

International collaborations

Academic Institutions

-Börje Sellergren, University of Malmö, Sweden,
-Ian Nicholls, University of Linnaeus, Sweden
-Knut Rurack, Federal Institute for Materials Research and Testing
-Panagiotis Manesiotis, Queen’s University, Belfast, United Kingdom
-Yongmin Zhang, Istitut Parisien de Chimie Moléculaire, Sorbonne University ,Paris, France
-Maria José Hernaiz Degano, Organic and Medicinal Chemistry department, Faculty of Pharmacy, Complutense University , Madrid, Spain

Funded active projects

Marie Skłodowska-Curie Actions (H2020-MSCA-ITN-2016, 722171-Biocapture)

Expertise

Competences

 -Full characterization of new molecules, API, intermediates. Isolation and full characterization of side-products and process impurities through 1D and 2D-NMR experiments, FTIR, HPLC and HRMS.
- Synthesis of MIP nanoparticles
- Development of enzymatic bioprocesses for the synthesis of API; chemoenzymatic synthesis of oligosaccharides and glyco-conjugated derivatives; semi-synthesis of glycoproteins (neo-glycoproteins); development of nano-biotechnological products of therapeutical relevance.

Instrumentations

- Biotage Initiator research microwave oven: Microwave system capable of processing organic reactions at controlled pressure and temperature conditions. Ideal tool for the synthesis of peptides, peptidomimetics, organic materials, and nano/polymer chemistry applications. - Biotage Isolera One automated flash purification system: Automated, medium pressure (up to 10 bar) liquid purification device exploitable for gram-scale peptides/glycopeptides fast purification working both in direct and reverse phase. Equipped with UV-VIS (200–800nm) detector and on-board computer with 10.4” capacitive touch screen interface.

Contacts

Ersilia De Lorenzi - ersidelo@unipv.it

Marco Terreni - marco.terreni@unipv.it

Massimo Serra - massimo.serra@unipv.it