Synthesis, Evaluation, Mechanistic Studies of Thiasugars and Their Dithia Derivatives for Application in Medicinal and Bioorganic Chemistry

Thioglycosides and thiasugars both have a long history in bioorganic and medicinal chemistry ^1-7 but it is widely considered that they are less “active” than the parent sugars. In our research, we sought to rationalize an application of thioglycosides, thiasugar glycosides, and their dithia-analogs in bio-organic and medicinal chemistry.We were driven by our discovery that the dithiasugar analogs of the short β-(1→3)-glucan, laminaritriose, showed comparable activity to the natural analog in the stimulation of phagocytosis and in the inhibition of anti-CR3 or anti-Dectin-1 fluorescein isothiocyanate (FITC)-conjugated antibody staining of human neutrophils and mouse macrophages ^{8, 9}. Building on those discoveries, we recently designed and synthesized tetravalent glycoclusters containing 1,5-dithialaminaribiose and -triose mimetics that showed comparable activity to the dithiasugar analogs described earlier¹⁰ in inhibition of anti-CR3 fluorescein isothiocyanate-conjugated antibody staining of human neutrophiles. To shed light on the unusual reactivity and selectivity of the glycosylation reactions with thiasugar substrates we performed low temperature NMR experiments to investigate the reactive intermediates formed during glycosylation reactions with thiasugars and investigate the generation and stability of simple thiocarbenium cations and their carbohydrate analogs. Finally, we wanted to investigate whether S-π interactions between glycosidic or endocyclic sulfur and aromatic residues of amino acids can influence the binding affinity with lectins and use the results of this study as a foundation for a predictive tool that can be used to identify cases when it is worth making thioglycosides or thiasugars. Collectively, this seminar will describe our synthetic efforts towards tetravalent glycoclusters, the study of the thiasugar reactivity with low-temperature NMR experiments, and the PDB database search to identify suitable examples wherein introduction of thioglycosides and thiasugars can be beneficial due to the S-π interactions.

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(5) Witczak, Z. J.; Poplawski, T.; Czubatka, A.; Sarnik, J.; Tokarz, P.; VanWert, A. L.; Bielski, R. A Potential CARB-Pharmacophore for Antineoplastic Activity: Part 1. Bioorg. Med. Chem. Lett. 2014, 24, 1752-1757.

(6) Szilágyi, L.; Varela, O. Non-Conventional Glycosidic Linkages: Syntheses and Structures of Thiooligosaccharides and Carbohydrates with Three-Bond Glycosidic Connections. Curr. Org. Chem. 2006, 10, 1745-1770.

(7) Sattin, S.; Bernardi, A. Design and Synthesis of Glycomimetics. Carbohydr. Chem. 2016, 41, 1-25.

(8) Liao, X.; Větvička, V.; Crich, D. Synthesis and Evaluation of 1,5-Dithia-D-laminaribiose, Triose and Tetraose as Truncated β-(1→3)-Glucan Mimetics. J. Org. Chem. 2018, 83, 14894-14904.

(9) Wen, P.; Vetvicka, V.; Crich, D. Synthesis and Evaluation of Oligomeric Thioether-Linked Carbacyclic β-(1→3)-Glucan Mimetics. J. Org. Chem. 2019, 84, 5554-5563.

(10) Ahiadorme, D.; Ande, C.; Fernandez-Botran, R.; Crich, D. Synthesis and evaluation of 1,5-dithialaminaribiose and -triose tetravalent constructs. Carbohydr. Res. 2023, 525, 108781. DOI: https://doi.org/10.1016/j.carres.2023.108781.