Synthesis of modified D-allohexofuranosyl-uracil nucleoside analogs
Petrova-Szczasiuk, Kseniia (2024-11-10)
Synthesis of modified D-allohexofuranosyl-uracil nucleoside analogs
(10.11.2024)
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Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2024111291060
https://urn.fi/URN:NBN:fi-fe2024111291060
Tiivistelmä
Abstract
The study of nucleosides, nucleotides, and their polymers is essential due to their critical roles in cellular processes such as DNA replication, RNA transcription, protein synthesis, signaling, and energy transfer. These molecules serve as the building blocks of life, making them fundamental to genetics, molecular biology, pharmacology, and other relevant scientific fields. Beyond their natural functions, chemically modified nucleosides, nucleotides, and their oligomers have emerged as powerful tools in medicine, biotechnology, and research. These advancements include the development of antiviral and anticancer therapies using modified nucleoside analogs, as well as therapies employing oligonucleotide-based treatments targeting pre-mRNA and mRNA. Furthermore, these modifications have enhanced diagnostic technologies and research tools. The ability to modify and efficiently synthesize these modified analogs and their oligomers opens new possibilities for therapeutic applications, offering improved stability, specificity, and efficacy.
This work builds on an extensive body of literature exploring the roles of nucleotides, nucleosides, and their modified analogs. Initially, the review covers the physiological significance of natural nucleos(t)ides, emphasizing their central role in genetic information transfer and cellular metabolism. Then focus shifts toward chemically modified nucleos(t)ides, which have become increasingly important in antiviral, anticancer, gene therapies, and biotechnological tools. Various synthetic strategies for altering sugar, nucleobase, and phosphate moieties are critically reviewed, with a particular emphasis on methods that enable precise structural alterations. Special attention is also given to the utility of D-allofuranose, an atypical sugar that served as a scaffold for modified nucleoside analogs developed in the practical part of this work. These insights underscore the potential of developing novel therapeutic agents with enhanced properties and directly inform the synthetic approaches. This review guided the selection of synthetic routes, protecting group strategies, and targeted modifications that were further practically explored in this study.
The experimental part of this research focused on synthesizing D-allofuranosyl-uracil analogs, with a special focus on modifying the 6’-hydroxyl group. The study explored the effectiveness of two different synthetic routes for the initial sugar configuration preparation, the separation of the α/β-anomer forms of the resulting uracil nucleosides, and the introduction of an azide group at the 6’OH-position. Despite encountering challenges, such as the unsuccessful addition of a triphosphate group, the research demonstrated the feasibility of synthesizing a modified nucleoside key intermediate. Further work is needed to optimize the phosphorylation process and fully evaluate the biological properties of consequently derived nucleotides’ antiviral properties.
The study of nucleosides, nucleotides, and their polymers is essential due to their critical roles in cellular processes such as DNA replication, RNA transcription, protein synthesis, signaling, and energy transfer. These molecules serve as the building blocks of life, making them fundamental to genetics, molecular biology, pharmacology, and other relevant scientific fields. Beyond their natural functions, chemically modified nucleosides, nucleotides, and their oligomers have emerged as powerful tools in medicine, biotechnology, and research. These advancements include the development of antiviral and anticancer therapies using modified nucleoside analogs, as well as therapies employing oligonucleotide-based treatments targeting pre-mRNA and mRNA. Furthermore, these modifications have enhanced diagnostic technologies and research tools. The ability to modify and efficiently synthesize these modified analogs and their oligomers opens new possibilities for therapeutic applications, offering improved stability, specificity, and efficacy.
This work builds on an extensive body of literature exploring the roles of nucleotides, nucleosides, and their modified analogs. Initially, the review covers the physiological significance of natural nucleos(t)ides, emphasizing their central role in genetic information transfer and cellular metabolism. Then focus shifts toward chemically modified nucleos(t)ides, which have become increasingly important in antiviral, anticancer, gene therapies, and biotechnological tools. Various synthetic strategies for altering sugar, nucleobase, and phosphate moieties are critically reviewed, with a particular emphasis on methods that enable precise structural alterations. Special attention is also given to the utility of D-allofuranose, an atypical sugar that served as a scaffold for modified nucleoside analogs developed in the practical part of this work. These insights underscore the potential of developing novel therapeutic agents with enhanced properties and directly inform the synthetic approaches. This review guided the selection of synthetic routes, protecting group strategies, and targeted modifications that were further practically explored in this study.
The experimental part of this research focused on synthesizing D-allofuranosyl-uracil analogs, with a special focus on modifying the 6’-hydroxyl group. The study explored the effectiveness of two different synthetic routes for the initial sugar configuration preparation, the separation of the α/β-anomer forms of the resulting uracil nucleosides, and the introduction of an azide group at the 6’OH-position. Despite encountering challenges, such as the unsuccessful addition of a triphosphate group, the research demonstrated the feasibility of synthesizing a modified nucleoside key intermediate. Further work is needed to optimize the phosphorylation process and fully evaluate the biological properties of consequently derived nucleotides’ antiviral properties.