Gray, Elspeth Jane; (1992) The synthesis of novel monosaccharides as potential anthelmintics. Doctoral thesis (Ph.D.), University College London.

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Abstract

The distribution and pathology of those filarial nematodes which affect man is reviewed, with particular emphasis on Onchocerca volvulus, the causative agent of onchocerciasis (River Blindness). The present control and drug treatment of onchocerciasis is outlined together with filarial carbohydrate metabolism, with a view to the rational development of selective novel chemotherapeutic agents. The results of several studies on parasitic glucose uptake inhibition are shown and discussed and the differing structural requirements of the human erythrocyte and parasite glucose uptake systems are compared. The identification of the primary synthetic target compound, 2-deoxy-5-thio-D-glucose is presented together with a short review of the known biochemistry of thio and amino sugars. An overall synthetic strategy is outlined and discussed, with the a review of past syntheses of 5-thio-D-glucose and 2-acetamido-2-deoxy 5-thio-D-glucose. The use and versatility of deoxyhalogeno sugars as intermediates in the synthesis of thio, amino and deoxy sugars is reviewed and discussed. Model studies on halogenation and displacement reactions of 3-O-acetyl-1, 2-0- isopropylidene-D-glucose are presented. The development of two novel synthetic routes to 2-acetamido-2-deoxy-5-thio-D glucose is described; the first based upon methyl glucofuranoside intermediates and the successful second route upon acyclic dimethyl acetal derivatives. The synthesis of both 2 acetamido-2-deoxy-5-thio-D-glucose and 2-acetamido-5-azido-2, 5-dideoxy-3, 4- 0 isopropylidene-aldehydo-D-glucose dimethyl acetal from a common intermediate is detailed and compared with literature syntheses. An attempted radical-induced reductive deamination of 2-acetamido-2-deoxy-5-thio-D- glucose to the 2-deoxy analogue is described. The development of synthetic routes towards a series of 2-acetamido-2-deoxy-4-thio and 4-amino sugars is described, including studies on the relative utility of various reagents for the selective benzoylation of N-acetylglucosamine. A synthesis of l,3,5,6-tetra-0-acetyl-2-acetamido-2-deoxy-4-thio-D-galactose is presented. The synthesis of some 4-chloro and 4-bromo galactopyranose derivatives is described in conjunction with studies on the ease of halogen displacement with thiocyanate, thioacetate and azide anions. The steric and electronic factors governing such displacements are discussed and compared with literature examples. The development of a novel synthetic route is outlined for the preparation of 4-thioglucose derivatives with overall retention of configuration.

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