Synthesis of Artificial Nucleotides for Biological Applications

by Elisa Santagostino
Doctoral thesis
Date of Examination:2025-01-10
Date of issue:2025-05-20
Advisor:Prof. Dr. Nadja A. Simeth
Referee:Prof. Dr. Kai Tittmann
Referee:Prof. Dr. Lutz Ackermann
Referee:Prof. Dr. Johannes C. L. Walker
Referee:Prof. Dr. Anna Krawczuk
Referee:Dr. Michael John
Persistent Address: http://dx.doi.org/10.53846/goediss-11237

 

 

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Abstract

English

This thesis explores the synthesis of nucleotides, the building blocks of DNA and RNA, two essential molecules in living cells. One project focused on developing a more effective ligand for orotidine-5’-monophosphate decarboxylase (OMPDC), a highly efficient enzyme that functions without cofactors. Despite its efficiency, the enzymatic mechanism is not yet fully understood. To gain deeper insights into the human OMPDC-substrate complex, we studied both known and novel analogues of the substrate (OMP) and product (UMP), aiming to design a more effective OMPDC inhibitor. The second project investigated phosphorodiamidate morpholino oligonucleotides (PMOs), promising nucleic acid analogues for gene modulation and therapeutic applications. However, PMOs contain a chiral phosphorus centre, leading to diastereomeric mixtures that may vary in biological activity. To address this challenge, we explored a novel methanediamine-based linker as a non-chiral alternative, revisited the synthesis of the known carbamate linker, and expanded the nucleobase alphabet for the reported glycine linker.
Keywords: OMPDC; enzyme catalysis; ligand design; nucleotide synthesis; PMOs; nucleic acid analogues; linker design
 
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