Synthesis of a new class of thio-glycomimetics through one-pot aziridine opening reactions

Session: 
S6.2 Lectins I
Code: 
OL6.2.1
Location (hall): 
Mannose
Start/end time: 
Tuesday, July 2, 2019 - 17:15 to 17:30
Nives
Hribernik

Nives Hribernik1, Alice Tamburrini1, Ermelinda Falletta1, Francesca Vasile1, Anna Bernardi1

1Dipartimento di Chimica, Università degli Studi di Milano, Milano, Italy

As the most abundant natural products, sugars encode a large amount of biochemical information. Development of glycomimetic structures allows manipulating their structural complexity, thus producing tools for investigation of biological processes and new drug development. The need for molecules with improved drug-like characteristics and metabolic stability has put thio-glycomimetics in the spotlight. [1,2]

The synthetic potential of thioglycosides presents further benefits; as they are stable under a wide range of conditions and yet interconvertible in a number of useful ways. Our group has recently developed a novel one-pot aziridine opening approach to the synthesis of N-linked-pseudo-thio-glycosides, providing an alternative to standard glycosylation procedures. [3] We successfully synthetized a first example of this new class of glycomimetics, N-linked-pseudo-thio-dimannoside 1 (Figure 1), addressed against DC-SIGN (Dendritic Cell-Specific ICAM3 Grabbing Non integrin). C-type lectin DC-SIGN is involved in recognition of viruses and pathogens on mucosal level and plays a role in HIV-1 transmission. [2] We showed that compound 1 binds to DC-SIGN with the same affinity of natural substrate 1,2-mannobioside and its previous mimic pseudo-1,2-dimannoside. [3]

Synthesis of these compounds requires a peracetylated thioglycoside and a conformationally locked aziridine 3 (Figure 1). In a facile one-pot reaction the aziridine ring selectively opens when attacked by a glycosyl thiol generated in situ, affording a single product via trans-diaxial opening.

We explored the scope of the reaction and optimized the conditions for various mono- and disaccharides, generating a library of compounds with the general structure of 4. These novel compounds can be potentially recognized by a wide range of lectins while providing resistance to glycosidases. Our current objective is to further exploit potentials of the structure for synthesis of pseudo-glycopeptides.

All the synthetic and mechanistic aspects will be discussed as well as possibilities to additionally functionalize these compounds.

Figure 1: Structure of N-linked-pseudo-thio-dimannoside 1 and one-pot aziridine opening reaction.

Acknowlegements

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 765581 (PhD4GlycoDrug).

References: 
  1. Driguez, H. Thiooligosaccharides as Tools for Structural Biology. CHEMBIOCHEM 2001, 2, 311-318.
  2. Tamburrini, A.; Achilli, S.; Vasile, F.; Sattin, S.; Vivès, C.; Colombo, C.; Fiesci, F.; Bernardi, A. Facile Access to Pseudo-thio-1,2-dimannoside, a New Glycomimetic DC-SIGN Antagonist. Bioorganic&Medicinal Chemistry 2017, 25, 5142-5147.
  3. Tamburrini A. One-pot Synthesis of Thio-glycomimetics Through Ring Opening Reactions, Ph.D. Thesis, University of Milan, January 2019.

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