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Title: Molecular construction of sulfonamide oligonucleotides
Author: Korotkovs, Valerijs
ISNI:       0000 0004 8503 1286
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2019
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Antisense oligonucleotides (ASO's) are a class of therapeutics that target RNA. Advancements in chemical modifications of oligonucleotides culminated in recent FDA approvals of three ASO's for the treatment of homozygous familial hypercholesterolemia (Kynamro), Duchenne muscular dystrophy (Eteplirsen), and spinal muscular atrophy (Spinraza). In this work, efforts towards an efficient and scalable synthesis of sulfonamide oligonucleotide monomers were developed for replacement of the phosphodiester linker of RNA by a sulfonamide-containing linker to allow construction of sulfonamide oligonucleotides. The synthesis of monomers is described through Chapters 2 to 4. Using the described monomers, it was possible to synthesise sulfonamide oligonucleotides in solution phase and some crucial properties of the resulting oligonucleotides like cell permeability were studied in Chapter 5.A sulfonamide-phosphodiester oligonucleotide chimera (SaDNA) was prepared by synthesising a sulfonamide Thymine-Thymine dimer compatible with phosphoramidite chemistry and incorporating it into a DNA sequence in Chapter 6. The resulting SaDNA was used in a thermal stability experiment to study SaRNA double-strand complexes with DNA and RNA. Although sulfonamide modification caused a decrease in melting temperature (Tm) the incorporated sulfonamide monomer displayed selectivity in binding to RNA. A preliminary experiment was performed using the prepared sulfonamide monomers to synthesise oligonucleotides on solid phase using a Rink amide-polystyrene resin in Chapter 7.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: QD Chemistry