Towards the synthesis of biologically active carbohydrates and carbohydrate mimetics

Drinnan, Nicholas Barry. (2004). Towards the synthesis of biologically active carbohydrates and carbohydrate mimetics PhD Thesis, Institute for Molecular Bioscience, The University of Queensland.

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Author Drinnan, Nicholas Barry.
Thesis Title Towards the synthesis of biologically active carbohydrates and carbohydrate mimetics
School, Centre or Institute Institute for Molecular Bioscience
Institution The University of Queensland
Publication date 2004
Thesis type PhD Thesis
Supervisor Dr Tracie Ramsdale
Dr Judy Halliday
Dr Jenny Martin
Total pages 214
Collection year 2004
Language eng
Subjects 270100 Biochemistry and Cell Biology
Formatted abstract

In its broadest sense, this body of research was commenced with the intention of developing facile methods for the synthesis of biologically relevant carbohydrates and carbohydrate like molecules, and potentially screening these molecules against relevant targets. The research was conducted in two parts. In part I, research was undertaken to examine the advantages and limitations of a novel linker N-1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde) system, as a tool for carbohydrate based syntheses. The Dde linker was a synthetic agent for solid phase synthesis that had previously shown some potential in solid phase carbohydrate synthesis1, but the scope of application of which was largely unexplored. A series of synthetic studies were undertaken to more fully realise the potential of the linker. It was believed that the Dde linker could satisfy some unmet needs in regard to the solid phase synthesis of carbohydrates, in particular, enabling the accomplishment of stereoselective syntheses with a high level of coupling per step, on a high loading resin. Further, it was believed that the Dde linker could ultimately prove useful as a tool in the synthesis of other diverse carbohydrate related structures. 


Accordingly, methods for coupling the linker to resin, and cleaving products from a resin linker conjugate were established. The synthesis of several oligosaccharides was then undertaken using a Dde resin-linker conjugate. Syntheses were able to be accomplished employing a high loading resin with effectively quantitative conversion at each step of synthesis conducted on solid support. A linear trisaccharide and a branched tetrasaccharide were successfully synthesised in high yield. Continuing the development of facile methods for the synthesis of biologically relevant carbohydrates, the suitability of Dde resin linker conjugates as a tool for solid phase enzymatic synthesis was investigated. In particular, it was considered desirable to effect enzymatic syntheses with sialyltransferases, in order to provide methods to avoid the numerous difficulties encountered when synthesizing sialic acid containing conjugates by chemical methods. Consequently, an N-acetyllactosamine moiety was coupled to Dde resin linker conjugate and successfully employed in the synthesis of a derivatised 6'-sialyl-N-acetyllactosamine. 


Following on from the studies in solid phase carbohydrate synthesis, and as a result of an interest developed in the biological roles of sialyltransferases, research in Part II was conducted towards developing methods for coupling potential sialic acid mimetics to carbohydrate scaffolds with the intention of synthesizing potential sialyltransferase inhibitors. An extensive review of sialyltransferase inhibitors was undertaken. Considerable research was found to have been conducted on donor and transition state inhibitors. It was determined that product based inhibitors have remained comparatively unexplored. Hence, the primary goal of Part II was to determine if sialyltransferases could be inhibited using a product based design. It was believed that the Dde linker system developed in Part I could be used as a synthetic agent for the synthesis of sialyltransferase inhibitors. To this end, studies were undertaken to determine the suitability of a Dde based resin bound lactosamine scaffold as a suitable agent for the development of mimetics of 6'-0-sialy-N-acetyllactosamine. For the purpose of this synthesis the resin-linker sugar conjugate proved unsuitable. Derivatised hydroxyphosphonate moieties were selected and synthesised as potential sialic acid mimetics. The initial building blocks chosen as a sialic acid mimetics proved to be unstable during the reactions conditions trialled to effect coupling of the group to a carbohydrate hydroxyl group. Further solution phase studies led to an appropriate hydroxyphosphonate derivative being chosen enabling the synthesis of a potential sialyltransferase inhibitor.

Keyword Carbohydrates -- Synthesis
Glycosides -- Synthesis
Polysaccharides -- Synthesis
Additional Notes

Variant title: Synthesis of carbohydrates and carbohydrate mimetics

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Created: Tue, 28 Feb 2012, 11:28:24 EST by Bekti Mulatiningsih on behalf of The University of Queensland Library