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DEVELOPMENT OF CATALYTIC GLYCOSYLATION METHOD FOR OLIGOSACCHARIDE ASSEMBLY AND TOTAL SYNTHESIS OF ACIDIC ALPHA-DYSTROGLYCAN OLIGOSACCHARIDES

SASMAL, ANIRUDDHA (2017) DEVELOPMENT OF CATALYTIC GLYCOSYLATION METHOD FOR OLIGOSACCHARIDE ASSEMBLY AND TOTAL SYNTHESIS OF ACIDIC ALPHA-DYSTROGLYCAN OLIGOSACCHARIDES. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

The field of glycoscience explores the structures and functions of carbohydrates that calls for the rapid access of structurally defined oligosaccharides. In contrast to the synthesis of nucleic acids and peptides/proteins, synthetic preparation of carbohydrates remains laborious that necessitates the development of novel yet robust synthetic strategy to achieve automated oligosaccharide synthesis.
In PART A of this thesis, we report our recent developments of a novel glycosylation method based on a designer thioglycoside that can be activated by catalytic amount of carbophilic Lewis acid. Furthermore, in two separate strategies i.e. 1) catalytic reactivity-based one-pot glycosylation and 2) sequential active-latent strategy for glycosylation, we will demonstrate the synthetic utility of our new methodology. We also identified perfluoroamide based linker in biomolecule synthesis. The fluorous solid phase extraction facilitates the solution-phase rapid oligosaccharide assembly. Gold-catalyzed glycosylation, clubbed with perfluoroamide linker/tag appeared to be an ideal recipe in the context of convenient combinatorial access to biologically important carbohydrate molecules.
In PART B, I address the important issue associated with the functions of carbohydrate modification in dystroglycan (DG) in muscular dystrophies (MDs), a group of muscle diseases, for which currently no cure is available. Sorting out the relationships between the various molecular defects in glycosylation and the modes of disease presentation is challenging. The enzymatic oligosaccharide product from LARGE gene has been recently identified, which consists of a repeating (13)-GlcUA--(13)-Xyl disaccharide unit. A template directed 1,2-cis glycosylation was utilized to synthesize a series of a-DG associated glycans. Additionally, a successful synthesis is demonstrated for B4GAT1 enzymatic trisaccharide, which is also found to be involved in post-translational modification. We expect our study serve as the basis for finding novel medical solutions to neurological diseases that commonly causes cardiac muscle dystrophies and brain diseases.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
SASMAL, ANIRUDDHAans142@pitt.eduANS142
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairLiu, Xinyuxinyuliu@pitt.eduxinyuliu
Committee MemberFloreancig, Paulflorean@pitt.eduflorean
Committee MemberWilcox, Craigdaylite@pitt.edudaylite
Committee MemberGold, Barrygoldbi@pitt.edugoldbi
Date: 29 September 2017
Date Type: Publication
Defense Date: 31 March 2017
Approval Date: 29 September 2017
Submission Date: 13 April 2017
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 509
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Catalytic Glycosylation, Gold catalyst, One-pot reactivity based glycosylation,latent-active glycosylation,perfluoroamide, acidic oligosaccharide, xylose-glucuronic acid, alpha-dystroglycan oligosaccharide.
Date Deposited: 29 Sep 2018 05:00
Last Modified: 29 Sep 2018 05:00
URI: http://d-scholarship.pitt.edu/id/eprint/31443

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