ANNALISA GUARAGNA

Room 0Mb017; phone +39-081-674119 Email annalisa.guaragna@unina.it ;

https://www.docenti.unina.it/annalisa.guaragna

http://orcid.org/0000-0001-8684-0622

Other Group members:

Maria De Fenza (PhD student), Anna Esposito (PhD student)]

Group web site: 

https://www.facebook.com/AG-Lab-270492170141098/?ref=br_rs

Research:

Mirror-Image Molecular Systems (MIMS): Revisiting the Role of Chirality at Chemistry-Biology Interface

L-Iminosugars: Emerging Glycomimetics

Sugar Modified Nucleosides: Biomimetics with antiviral potential

Smart Drug Delivery Systems

Mirror-Image Molecular Systems (MIMS): Revisiting the Role of Chirality at Chemistry-Biology Interface

Bioactive chiral molecules often hold specific conformational and high-order structures associated with their stereochemical features; their structures are deeply connected with their properties and functions, including the ability for chiral recognition. Nevertheless, the relationships between stereochemistry of a bioactive molecule and its effective biological function are not always predictable. Even though it is often assumed that biomolecular recognition processes are stereospecific, many exceptions involving "mirror-image" bioactive compounds suggest that enantiospecificity could not be an universal trait related to biological function. Our investigations on MIMS exploit a synthetic method enabling preparation of enantiopure organic molecules by a three-carbon homologation of chiral electrophiles. This has led to the synthesis of a great amount of compounds with potential antiviral (nucleoside analogues, iminosugars) and antisense (Homo-DNA, HNA, Imino-HNA) properties. Study of the conformational implications associated to such systems have led to intriguing results regarding diverse biomolecular recognition processes.

Main collaboration:

Prof. Arthur van Aerschot Department of Pharmaceutical and Pharmacological Sciences, Rega Institute for Medical Research Leuven, Belgium

Prof. Piet Herdewjin Department of Pharmaceutical and Pharmacological Sciences, Rega Institute for Medical Research Leuven, Belgium

Selected publications:

• Daniele D'Alonzo, Mathy Froeyen, Guy Schepers, Giovanni Di Fabio, Arthur Van Aerschot, Piet Herdewijn, Giovanni Palumbo, and Annalisa Guaragna, ‘1',5'-Anhydro-L-ribo-Hexitol Adenine Nucleic Acids (alpha-L-HNA-A): Synthesis and Chiral Selection Properties in the Mirror Image World' J. Org. Chem. (2015), 80, 5014.
• Daniele D'Alonzo, Jussara Amato, Guy Schepers, Mathy Froeyen, Arthur Van Aerschot, Piet Herdewijn, Annalisa Guaragna ‘Enantiomeric selection properties of β-homoDNA: Enhanced pairing for heterochiral complexes' Angew. Chem., Int. Ed. (2013), 52, 6662
• Daniele D'Alonzo, Arthur Van Aerschot, Annalisa Guaragna, Giovanni Palumbo, Guy Schepers, Stefania Capone, Jeff Rozenski, Piet Herdewijn ‘Synthesis and Base Pairing Properties of 1',5'-Anhydro-L-Hexitol Nucleic Acids (L-HNA)' Chem.-Eur. J. (2009), 15, 10121.
• Annalisa Guaragna, Stefano D'Errico, Daniele D'Alonzo and Giovanni Palumbo ‘A General Approach to the Synthesis of 1-Deoxy-L-Iminosugars' Org. Lett. (2007), 9, 3473.
• Annalisa Guaragna, Carmela Napolitano, Daniele D'Alonzo and Giovanni Palumbo ‘A Versatile Route to L-Hexoses: Synthesis of L-Mannose and L-Altrose' Org. Lett. (2006), 8, 4863.]

L-Iminosugars: Emerging Glycomimetics

Iminosugars represent the most promising class of therapeutically useful glycomimetics. Because of their ability to mimic structure and properties of natural monosaccharides, iminosugars are able to interfere with disease-related carbohydrate-processing enzymes. Despite their great therapeutic potential, iminosugars suffer of poor selectivity, thereby leading to the onset of undesired side effects after prolonged administration. A valid alternative is offered by L-iminosugars, the non-superimposable mirror images of natural iminosugars which can act as either inhibitors or chaperones of various glycosidases, although working in a more markedly selective manner. The study on L-iminosugars has been widened to N-alkyl-L-iminosugars. Some of them are able to enhance lysosomal α-glucosidase levels in Pompe disease fibroblasts, or to exhibit an anti-inflammatory effect in Cystic Fibrosis (CF) bronchial cells, by targeting β-glucosidase 2 (GBA2). N-alkyl-L-iminosugars are currently object of studies aimed to assess their pharmaceutical potential for the treatments of re- and emerging tropical diseases.

Main collaboration:

Prof. Giancarlo Parenti Department of Translational Medical Sciences, Section of Pediatrics, Università degli Studi di Napoli Federico II, Napoli, Italy. Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.

Prof. Marco Moracci Institute of Biosciences and Bioresources, Consiglio Nazionale delle Ricerche, Napoli, Italy. Department of Biology, Università degli Studi di Napoli Federico II, Napoli, Italy.

Prof. Frances Platt Department of Pharmacology, Medical Sciences Division, University of Oxford, UK.

Dr Maria Cristina Dechecchi and Prof. Giulio Cabrini Department of Pathology and Diagnostics. University Hospital of Verona, Verona, Italy,

Dr Alessandra Bragonzi CFaCore, Infection and CF Unit, San Raffaele Scientific Institute,

Prof. Nicole Zitzmann Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford

Selected publications:

• Daniele D'Alonzo, Maria De Fenza, Caterina Porto, Roberta Iacono, Mylene Huebecker, Beatrice Cobucci-Ponzano, David A. Priestman, Frances Platt, Giancarlo Parenti, Marco Moracci, Giovanni Palumbo, and Annalisa Guaragna ‘N-Butyl-L-deoxynojirimycin (L-NBDNJ): Synthesis of an Allosteric Enhancer of α-Glucosidase Activity for the Treatment of Pompe Disease' J. Med. Chem. (2017), 60, 9462.
• Daniele D'Alonzo, Annalisa Guaragna., Giovanni Palumbo ‘Glycomimetics at the Mirror: Medicinal Chemistry of L-Iminosugars' Curr. Med. Chem. (2009), 16, 473.
• Annalisa Guaragna, Antonio Dell'Isola, Stefano D'Errico, Giovanni Palumbo, Daniele D'Alonzo ‘Beyond Achmatowicz Reaction: DDQ-mediated Chemo- and Stereoconvergent Domino-One Pot Cyclization/Rearrangement of bis-Thioenol Ether-Containing Chiral Building Blocks' Tetrahedron Lett. (2014), 55, 7007.
• Daniele D'Alonzo, Annalisa Guaragna, Concetta Paolella, Giovanni Palumbo ‘Synthesis of 1-Deoxy-L-Gulonojirimycin and 1-Deoxy-L-Talonojirimycin' Tetrahedron Lett. (2009), 50, 2045.
• Annalisa Guaragna, Stefano D'Errico, Daniele D'Alonzo, Silvana Pedatella and Giovanni Palumbo ‘A General Approach to the Synthesis of 1-Deoxy-L-Iminosugars' Org. Lett. (2007), 9, 3473.

Sugar Modified Nucleosides: Biomimetics with antiviral potential

In the absence of effective vaccines able to control viral infections, clinical use of chemically modified nucleosides currently represents the core of any chemotherapeutic treatment aiming at a substantial and prolonged suppression of viral replication. Because of the structural relationship with their natural counterparts, synthetic nucleosides can deeply interfere with various viral life cycles, mainly at a transcriptional level, by blocking the information flow enclosed in the viral genomes. Among sugar-modified nucleosides, those having an unnatural five- or six-membered heterocyclic moiety (with both D- or L-configuration) as deoxyribose bioisostere have received considerable attention over the last two decades, owing to their remarkable antiviral properties. Our recent interest has been devoted to a more convenient and stereoselective method for the preparation of the well-known anti-HIV drug Lamivudine, and to the synthesis of six-membered carbocyclic nucleosides as well as of iminosugars-based nucleoside to be evaluated as new broad spectrum antiviral drugs.

Main collaboration:

Johan Neyts, Department of Virology , Rega Institute for Medical Research, Leuven, Belgium

Dr Graciela Andrei, Department of Microbiology and Immunology, Rega Institute for Medical Research, Leuven, Belgium

Selected publications:

• Daniele D'Alonzo, Maria De Fenza, Giovanni Palumbo Valeria Romanucci, Armando Zarrelli, Giovanni Di Fabio, Annalisa Guaragna ‘Synthesis of beta-L-2'-Fluoro-3'-Thiacytidine (F-3TC) Stereoisomers: Toward a New Class of Oxathiolanyl Nucleosides?' Synthesis (2017), 49, 998.
• Federica M. Caso, Daniele D'Alonzo, Stefano D'Errico, Giovanni Palumbo, Annalisa Guaragna ‘Highly Stereoselective Synthesis of Lamivudine (3TC) and Emtricitabine (FTC) by a Novel N-Glycosidation Procedure' Org. Lett. (2015) 17, 2626.
• Concetta Paolella, Daniele D'Alonzo, Giovanni Palumbo, Annalisa Guaragna ‘Sulfur-assisted domino access to bicyclic dihydrofurans: Case study and early synthetic applications' Org. Biomol. Chem. (2013) 11, 7825.
• Concetta Paolella, Daniele D'Alonzo, Annalisa Guaragna, Flavio Cermola, Giovanni Palumbo ‘Synthesis of 2,3-Dihydro-1,4-Dithiinyl Nucleosides via Pummerer-Type Glycosidation', Tetrahedron Lett. (2010) 51, 6060.

Smart Drug Delivery Systems

A long-standing problem in cancer chemotherapy is the lack of tumor-specific treatments. Traditional therapy relies on the action of cytotoxic agents; unfortunately, they have very little or no specificity, leading to systemic toxicity and causing severe side effects. Therefore, the construction of smart drug delivery systems, which enable selective release of cytotoxic drug at the disease's site, is urgently needed. Our project is focused on the synthetic development of new molecular systems (carrier-linked prodrugs) able to be selectively internalized into tumor cells on the basis of the so-called "Trojan horse" strategy. Such approach relies on the use of a tumor recognition moiety (the folic acid), able to identify cancer cells as the target site, to which a cytotoxic agent (chlorambucil) is covalently bound by a suitable linker (oligoether or oligo-b-peptide chains). Thus, internalization of such molecular system allows entry of the prodrug into the cancer cell, in which the drug is then released by some intracellular events such as the intense enzymatic activity in cancer cells or by the strongly acidic medium of the lysosomes of tumor cells

Selected publications:

• Annalisa Guaragna, Giovanni N. Roviello, Stefano D'Errico, Concetta Paolella, Giovanni Palumbo, Daniele D'Alonzo ‘Solid phase synthesis of a novel folate-conjugated 5-aminolevulinic acid methyl ester based photosensitizer for selective photodynamic therapy' Tetrahedron Lett. (2015), 56, 775.
• Annalisa Guaragna, Angela Chiaviello, Concetta Paolella, Daniele D'Alonzo, Giuseppe Palumbo, Giovanni Palumbo ‘Synthesis and Evaluation of Folate-based Chlorambucil Delivery Systems for Tumor-Targeted Chemotherapy' Bioconjugate Chem. (2012), 23, 84.