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Title: The synthesis of phosphonate analogues of carbohydrates
Author: Moore, Sarah G.
ISNI:       0000 0004 2695 5243
Awarding Body: The University of Manchester
Current Institution: University of Manchester
Date of Award: 1998
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This t~esis is concerned with the synthesis of phosphonate analogues of carbohydrates as stable lsosteres of the corresponding phosphates. Analogues of glucose-6-phosphate (Part A) and mannose-6-phosphate (Part B) were prepared. Part A Glucose-6-phosphatase plays a central role in the homeostatic regulation of blood glucose, by catalysing the conversion of glucose-6-phosphate to glucose in the terminal steps of both gluconeogenesis and glycogenolysis. Abnormally high glucose-6- phosphatase activity has been noted in some cases of diabetes mellitus. Phosphonate analogues of glucose-6-phosphate (which contain a P-C linkage in place of the P-O-C moiety of the corresponding phosphate) are potential inhibitors of glucose-6-phosphatase and therefore could have an application in the treatment of diabetes. Here, the syntheses of three phosphonate analogues of glucose-6-phosphate are described. A non-isosteric phosphonate analogue (in which the phosphate bridging oxygen of glucose-6-phosphate has been removed) was prepared in seven steps from D-glucose, the key step being an Arbuzov reaction between triethyl phosphite and a benzyl protected glucose-6-bromide. Isosteric and isoelectronic phosphonate analogues (in which the bridging oxygen of glucose-6-phosphate has been replaced by a methylene [CH2] and a difluoromethylene [CF2] group, respectively) were also synthesised in seven steps from D-glucose, the key step being the nucleophilic attack of anion (EtO)2P(O)CX2- (X = H, F) on the C-6 triflate of a benzyl protected glucose derivative. PartB Transforming growth factor-~l (TGF-~l) is one of several cytokines implicated in scarring during adult wound healing. TGF-~l is stored in an inert form and activation is due, in part, to the binding of mannose-6-phosphate residues on latent TGF-~l to the mannose-6-phosphate/insulin-like growth factor-II (M-6-PIIGF-II) receptor. Phosphonate analogues of mannose-6-phosphate could inhibit TGF-~l activation by competitive inhibition of binding of latent TGF-~l to the M-6-PIIGF-II receptor and therefore have antiscarring potential. A non-isosteric phosphonate analogue of mannose-6-phosphate was prepared in eight steps from D-mannose utilising Arbuzov chemistry. Initial evaluation in a rat model indicated an anti-scarring effect. An a-hydroxy phosphonate analogue of mannose-6-phosphate was prepared utilising a Pudovic reaction between the anion of dibenzyl phosphite and the C-6 aldehyde of a benzyl protected mannose derivative. The Pudovic reaction proceeded with a diastereoisomeric excess of -80 % and various attempts were made to determine the absolute configuration of the major diastereoisomer. Several esterified derivatives were prepared in an attempt to obtain crystals suitable for X-ray analysis, however only oils or fine powders were formed. Reactions designed to synthesise conformationally restricted analogues in order to determine the conformation by NOE NMR spectroscopy are also described, however these were not successful. Phosphorylated a-I,2-linked mannobiosides are known to bind strongly to the M- 6-P/IGF-II receptor, and therefore an a-I,2-linked mannose disaccharide with a nonisosteric phosphonate at the non-reducing terminus was prepared. The coupling of a thioglycoside donor bearing a 6-phosphonate with the 1,3,4,6-tetra-O-acetyl-~-Dmannopyranoside acceptor was achieved with the use of the mild activator, Niodosuccinimide. Finally, methodology towards the synthesis of a bidentate ligand incorporating two mannose-6-phosphate groups, together with. the a-I ,2-mannosi~ic linkage is described. A cyclohexane-I,2-diacetal protected a-I ,2-hnked mannose dlsacchande _ beanng a 6- phosphonate moiety at the non-reducing terminus was prepared from protected monosaccharides, again using a mild activation procedure.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available