Date of Graduation

5-2021

Document Type

Thesis

Degree Name

Master of Science in Chemistry (MS)

Degree Level

Graduate

Department

Chemistry & Biochemistry

Advisor/Mentor

McIntosh, Matthias C.

Committee Member

Moradi, Mahmoud

Second Committee Member

Fan, Chenguang

Keywords

Carbohydrates; Glycosidase inhibitors; Glycoside hydrolase; Inhibitor; Synthesis

Abstract

Glycosidases are amongst the most abundant enzymes in nature. This is due to their role in the degradation of carbohydrates which are the major source of carbon or earth. The absence or malfunction of glycosidases is implicated in numerous diseases such as cancers, diabetes, and lysosomal storage disorders, which make them important drug targets for study in medicinal chemistry. The seminal work by Pauling and Wolfenden showed that enzymes bind to their substrate at the transition state with very strong affinity. Wolfenden estimated the dissociation constant to be around 10-22M. This encouraged the design of glycosidase inhibitors which mimicked one or more features of the transition state. The notable features of the transition state of glycosidases include the development of a positive charge on the anomeric carbon atom, and the distortion of the sugar ring into one of a boat, an envelope, or a half-chair conformation to accommodate the formed positive charge.

The glyconoamidine family of inhibitors emerged as a class of compounds to mimic both the positive charge and distorted chair conformation of the transition state of glycosidases. Research in the Striegler group identified a library of galactonoamidines as highly potent competitive inhibitors of several β-galactosidases, with inhibition constants in the low nanomolar to picomolar range. The work described here summarizes an effort towards the synthesis of polar and bulky galactonoamidines for the inhibition of the human α-galactosidase. Following a protocol previously established in the group, the precursor galactothionolactam was synthesized and coupled with several amines to yield a library of perbenzylated galactonoamidines. Hydrogenation of the perbenzylated galactonoamidines in the presence of palladium on carbon afforded some of the desired compounds, whereas the others were unsuccessful.

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