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FLUORINATED SUGARS: CHEMICAL TOOLS FOR THE STUDY OF CARBOHYDRATE-BINDING PROTEINS

Final Report Summary - FGLYP (FLUORINATED SUGARS: CHEMICAL TOOLS FOR THE STUDY OF CARBOHYDRATE-BINDING PROTEINS)

This project focuses on the preparation of potentially biologically active fluorinated glycoconjugates (mainly lipids, amino acids, peptides and eventually proteins) and also to explore the biological and biophysical properties of these molecules in vitro and in living cells that are decorated with these unnatural fluorinated elements on their surfaces. To tackle this general objective, the project initially focuses on the preparation of a set of fluorinated carbohydrates and lipids with configurations related to those recognized by lectins. The synthesis of fluorinated carbohydrates and lipids is carried out selecting in each case the most direct way reported in the literature, or via the development of new procedures based on carbohydrate chemistry or asymmetric synthesis. The next step consists of attaching the prepared fluorinated materials to the corresponding aglycons, amino acids, peptides or proteins (in the case of F-carbohydrates) or to the corresponding sugars in the case of F-lipids. The second part of the project aims to evaluate the conformation of these F-glycoconjugates through the use of leading spectroscopic techniques (mainly 19F STD-NMR, X-ray, etc.). This provides valuable information on how these molecules interact with target proteins or receptors. A brief summary of the work developed and the results obtained is listed below:

1. We have efficiently developed a methodology for accessing a series of neo-glycolipids with galacto configuration and different groups at C-2 position (F, OH, H and NHAc).
2. The interaction of those glycolipids (forming micelles with a detergent due to their poor solubility in water) with a model galactose-binding lectin viscum album agglutinin (Viscumin – VAA) was evaluated using leading spectroscopic techniques (1H and 19F-DOSY/STD/trNOE-NMR experiments, etc.).
3. We have synthesized 2-deoxy-2-fluorohexopyranoses with different configurations (gluco, galacto, manno) and anomeric linkages (N3, S, Se) for chemical protein modification.
4. We have synthesized 1-chalcogenopyranoses with different configurations (gluco, galacto) and anomeric linkages (S, S2, Se and Se2) as potential antioxidant agents for vascular disease treatment.
5. We have developed a general strategy for the synthesis of 2-CF3-glycals. The use of reliable, efficient cross-coupling of 2-iodoglycals with fluoroform-derived CuCF3 proceeds with complete regioselectivity at C-2 and enables access to 2-CF3-glycals with different configurations in excellent yields.
6. The stereoselective synthesis of important fluorinated precursors (2-Fpyranose, 2,2’-diFpyranose and 2-Fglycal) with different protecting groups (Ac, Bn) from D-glycals was achieved.
7. The preparation of key intermediates that will give access to fluorosugars with rare configurations/substitution patterns through olefination-cyclization-glycosylation reactions was explored.
8. We have explored different routes towards the preparation of perfluorinated analogues of KRN7000.
9. We have synthesized a series of multivalent glycolipids that mimic the clustering of ligands usually found in biological receptors.