Synthesis of 2-deoxy mucin-type O-glycans as biological probes

Abstract

Herein in presented the design, synthesis, and biological evaluation of a structurally diverse and stereochemically well-defined library of 2-deoxy glycoside analogues of the biologically relevant human mucin O-glycan structures.

Chapter 1 presents a background to the project, contextualising the work within the fields of 2 deoxy glycoside synthesis, carbohydrate-multivalent interactions, mucin glycan biology and mucin glycan analogues. Chapter 2 then sets out the aims of the project to synthesise a library of mucin-type O-glycans to bring all of the above research areas together.

Chapters 3 and 4 detail the synthetic routes used to access these analogues, with the synthetic strategy being based on glycal activation chemistry developed within the Galan group. The syntheses employ an orthogonal protecting group strategy using per-silylated donors, which allows for the incorporation of an anomeric linker bearing a reactive azido functionality for subsequent conjugation to a probe or platform via a Huisgen 1,3-dipolar cycloaddition (“click chemistry.”)

The uses and initial biological evaluation of these novel mucin-type O-glycans is documented in Chapter 5, where the orthogonality of the azide functionality is exploited in the formation of a variety of novel multivalent carbohydrate-containing structures, such as glycodendrons 208 to 214. The biological activity of some of these probes has been evaluated in bacterial agglutination assays for the detection of urinary tract infections with collaborators FluoretiQ Ltd. Additionally, galectin binding studies have indicated that some of these compounds bind with millimolar to micromolar e.g., compound 99) affinity.

These initial evaluations highlight the promising activity displayed by some of these analogues (e.g., glycodendron 210 in the agglutination assay or disaccharide 99 in the lectin binding studies) which bodes well for future investigations and generation of further mucin-type O-glycan analogues.

Date of Award	6 Dec 2022
Original language	English
Awarding Institution	University of Bristol
Supervisor	M C Galan (Supervisor)