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Dynamic Sulfur Chemistry :Screening, Evaluation and Catalysis

by Caraballo, Rémi, PhD

Abstract (Summary)
This thesis deals with the design, formation and evaluation of dynamic systems constructed by means of sulfur-containing reversible reactions, in organic and aqueous media and under mild conditions.In a first part, the synthesis of thioglycoside derivatives, constituting the biologically relevant starting components of the dynamic systems, is described. In addition, the pD-profile of the mutarotation process in aqueous media for a series of 1-thioaldoses is reported and revealed an astonishing beta-anomeric preference for all the carbohydrate analogs under acidic or neutral conditions.In a second part, the phosphine-catalyzed or -mediated disulfide metathesis for dynamic system generation in organic or aqueous media is presented, respectively. The direct in situ 1H STD-NMR resolution of a dynamic carbohydrate system in the presence of a target protein (Concanavalin A) proved the suitability and compatibility of such disulfide metathesis protocols for the discovery of biologically relevant ligands.In a third part, hemithioacetal formation is demonstrated as a new and efficient reversible reaction for the spontaneous generation of a dynamic system, despite a virtual character of the component associations in basic aqueous media. The direct in situ 1H STD-NMR identification of the best dynamic beta-galactosidase inhibitors from the dynamic HTA system was performed and the results were confirmed by inhibition studies. Thus, the HTA product formed from the reaction between 1-thiogalactopyranose and a pyridine carboxaldehyde derivative provided the best dynamic inhibitor.In a fourth and final part, a dynamic drug design strategy, where the best inhibitors from the aforementioned dynamic HTA system were used as model for the design of non-dynamic (or “static”) beta-galactosidase inhibitors, is depicted. Inhibition studies disclosed potent leads among the set of ligands.
Bibliographical Information:

Advisor:

School:Kungliga Tekniska högskolan

School Location:Sweden

Source Type:Doctoral Dissertation

Keywords:NATURAL SCIENCES; Chemistry; NATURAL SCIENCES; Chemistry; Organic chemistry; NATURAL SCIENCES; Chemistry; Organic chemistry; Bioorganic chemistry; Dynamic combinatorial chemistry; dynamic sulfur chemistry; thioglycoside; mutarotation; disulfide metathesis; hemithioacetal formation; 1H STD-NMR; inhibition; phosphine; Concanavalin A; beta-galactosidase; dynamic drug discovery.

ISBN:978-91-7415-618-8

Date of Publication:01/01/2010

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