ORCID

https://orcid.org/0009-0003-3054-0841

Date of Award

2026

Document Type

Dissertation

Degree Name

Pharmaceutical Sciences (Ph.D.)

Department

Pharmaceutical Sciences

First Advisor

Carlos A Sanhueza

Second Advisor

Vijaya Korlipara

Third Advisor

Sabesan Yoganathan

Abstract

Carbohydrates play critical roles in biological processes such as cell–cell communication, immune recognition, and host–pathogen interactions. These functions arise from their ability to adopt diverse three-dimensional structures that are selectively recognized by carbohydrate-binding proteins, including lectins. Unlike many biomolecules, carbohydrates exhibit significant conformational flexibility due to rotational freedom about glycosidic linkages and exocyclic substituents. Consequently, subtle variations in stereochemistry, aglycone structure, and solvent environment can modulate conformational equilibria and influence molecular recognition. Understanding these structural factors is essential for the rational design of glycomimetics and carbohydrate-based therapeutics. This dissertation investigates how steric and electronic variations at the anomeric position influence carbohydrate conformation and examines their impact on carbohydrate–protein interactions. A series of alkyl and aryl glycosides was synthesized using stereoselective glycosylation methods and characterized by multidimensional NMR spectroscopy. Conformational analysis focused on the C5–C6 hydroxymethyl group, which exists in gauche–gauche (gg), gauche–trans (gt), and trans–gauche (tg) conformations. Rotamer populations were determined from vicinal coupling constants. Increasing alkyl aglycone steric bulk shifted populations from gg toward gt, while electron-withdrawing aryl substituents produced similar trends. Solvent polarity further modulated these equilibria, with more pronounced effects observed in polar environments. Sulfur-linked glycosides exhibited increased flexibility relative to oxygen-linked analogues. These effects were extended to (1→6)-linked disaccharides, where increased conformational freedom enabled evaluation of aglycone-induced modulation in more complex systems. Steric bulk promoted gt conformations in protected derivatives, while solvent interactions partially attenuated these effects in deprotected analogues. The relationship between conformation and biological recognition was examined using Concanavalin A (ConA). Binding affinities and thermodynamic parameters were determined by isothermal titration calorimetry. Variations in binding correlated with ligand conformational properties, indicating that aglycone modifications influence lectin recognition through changes in conformational accessibility and solvation. Overall, this work demonstrates that steric and electronic modulation at the anomeric position provides an effective strategy for tuning carbohydrate conformational equilibria and offers a framework for the rational design of optimized glycomimetics and carbohydrate-based therapeutics.

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