Conjugation of oligonucleotides for drug delivery via a linker derived from Meldrum’s acid and A capture-release method to synthesize long oligonucleotides

Click chemistry offers a versatile approach for linking modular units via simple chemical reactions under mild conditions, often in benign solvents. Our research explores the conjugation of biomolecules using Meldrum’s acid derivatives as linkers, facilitating the stepwise attachment of an amine and a thiol under mild and neutral aqueous conditions. This methodology uniquely enables the subsequent decoupling reaction with a specific chemical trigger. A novel aspect of this research is the substitution of dithiothreitol which is not naturally present in biological systems, with cysteine and glutathione as the biologically available decoupling agents. Our work optimized the conjugation reactions and release mechanisms, with the goal of developing a highly tunable and sustainable drug delivery agent. This thesis also describes a new catch and release method for DNA purification. This method has potential to simplify the isolation of full-length long oligonucleotides. For this project we aimed for the synthesis of a propargylated glycerol phosphoramidite as a 5’-end label. Incorporation of this alkyne into oligonucleotides by solid-phase synthesis will enable the capture of the full-length sequences using azido-modified magnetic beads through a Copper-Catalyzed Azide–Alkyne Cycloaddition reaction. Subsequent ammonolysis reaction will release the unmodified full-length oligonucleotide sequences without the need for extensive purification.

Name thesis:degree_name

M.Sc. Chemistry

Level thesis:degree_level

Master

Discipline thesis:degree_discipline

Faculty of Mathematics and Science

Department dc:contributor.department

Department of Chemistry

Grantor dc:publisher

Brock University

Year dc:date.issued

2026

Author dc:creator

• Shahmoradi, Donya

• NATURAL SCIENCES::Chemistry::Organic chemistry::Organic synthesis
• MEDICINE
• NATURAL SCIENCES::Chemistry
• NATURAL SCIENCES::Chemistry::Organic chemistry
• NATURAL SCIENCES::Chemistry::Organic chemistry::Pharmaceutical chemistry

Language dc:language.iso

eng

Handle dc:identifier.uri

https://hdl.handle.net/10464/20003

OAI identifier oai:identifier

oai:brocku.scholaris.ca:10464/20003