Author:

Abstract:

Synthetic analogues of nucleosides, nucleotides and oligonucleotides have found application in the life-saving treatment of cancers and viral infections. High-affinity binding oligonucleotides have potential in the development of antisense, siRNA, aptamer and xeno nucleic acids (XNAs) research. These synthetic mimics usually carry modifications of either one or more of the essential components of the nucleic acid, such as nucleobase, sugar and phosphate. The vast amount of synthetic data and their biochemical properties are available to the research community for the base and sugar modified synthetic nucleosides. Sugar modification along with modification in internucleotide phosphate bond is relatively still unexplored. Hexitol nucleosides are the only six-membered sugar analogues which showed promising antiviral activities to date. In addition, with regard to the corresponding oligomers, hexitol nucleic acids (HNA) demonstrated the ability to fold into helical structures as well as form stable hybrids with natural counterparts, by reproducing the A-type form of dsRNA. HNA has also been proven to act as xenobiotic genetic material (XNA) capable of evolution in vitro while directing DNA synthesis in E. coli. In this PhD project, we explored the synthesis of pentopyranoside nucleoside phosphonate as the phosphonate mimetics of hexitol nucleoside monophosphate. Different strategies were explored and discussed. Detailed solution conformational analyses of all the four final nucleoside phosphonate products were carried out using NMR spectroscopy. According to NMR studies, the solution conformation of such pentopyranoside nucleoside phosphonates prefers an equatorial orientation of the nucleobase that circumvents unfavourable 1,3-diaxial interactions, in contrast to HNA nucleosides. Preliminary antiviral activities and incorporation tests are also investigated. Antiviral tests for adenine and thymine nucleoside phosphonates revealed that they are devoid of activity. Preliminary primer incorporation reactions using a mesophilic and thermophilic polymerase revealed that these phosphonate mimics are potentially useful monomers for medical and biotechnological applications.