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Synthesis and studies of carbohydrate mimetics as glycosidase inhibitors and molecular switches

Author

Barbora Brazdova, University of the Pacific

Date of Award

2006

Document Type

Dissertation - Pacific Access Restricted

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Drug Discovery and Chemical Synthesis

First Advisor

Vyacheslav Sameshin

First Committee Member

Andreas Franz

Second Committee Member

Silvio Rodriguez

Third Committee Member

David Fries

Fourth Committee Member

Xin Guo

Abstract

Part I . We explored the synthesis of a C -glycoside synthesis from L-fucose and malononitrile in the presence of a base catalyst. The reaction was much faster than the previously studied Henry condensation, and went further---to a double cyclization of 2:1 adduct with a novel dioxabicyclic structure. It provides a new route for the synthesis of chiral polysubstituted dihydropyrans and dihydropurans. A series of carbasugars was synthesized and tested for inhibitory activity towards fungal glycosidases from Aspergillus oryzae and Penicillium canescens . In order to reveal the dependence of inhibition on the alkyl group R, several derivatives with variable alkyl chain lengths were prepared and screened. Part II . Cyclohexane-based conformationally controlled ionophores, an emerging new class of molecular switches, provide a new and promising approach to allosteric systems with negative cooperativity. Protonation of trans -2-aminocyclohexanols was observed to cause dramatic conformational changes: due to an intramolecular hydrogen bond, a conformer with equatorial position of ammonio- and hydroxy-groups becomes predominant. This signal is mechanically transmitted by the structure of the molecule, inducing a conformational change in the second site and decreasing its affinity for an appropriate guest. Thus, these structures can serve as powerful conformational pH-triggers. The trans -2-aminocyclohexanol moiety has been used for pH-triggered conformational switching of crown ethers and podands, and their complexes with metal ions. The variation of the NR 2 group allows broad tuning of the conformational equilibrium, and thus tuning of the complexing ability of these allosteric ionophores. Heterotropic allosteric systems with high negative cooperativity may find many applications, such as membrane transport and drug delivery.

Pages

271

ISBN

9780542929038

Recommended Citation

Brazdova, Barbora. (2006). Synthesis and studies of carbohydrate mimetics as glycosidase inhibitors and molecular switches. University of the Pacific, Dissertation - Pacific Access Restricted. https://scholarlycommons.pacific.edu/uop_etds/2651