Synthesis and studies of nucleoside analogues in triplex forming oligonucleotides

Powers, Victoria Ellen Clare (2005) Synthesis and studies of nucleoside analogues in triplex forming oligonucleotides. University of Southampton, Doctoral Thesis.

Record type: Thesis (Doctoral)

Abstract

Triplex forming oligonucleotides (TFOs) are site specific agents that bind to the major groove of nucleic acid duplexes via specific hydrogen bonds. They have the potential to modulate gene activity in vivo (antigene strategy) and have been investigated as drugs against a variety of diseases such as cancer and bacterial or viral infections.

Despite their potential as selective DNA target agents, TFOs suffer from several limitations. Firstly, parallel triplex formation requires conditions of low pH (<6.0), necessary for formation of the C⁺.GC triplet. Secondly, triplexes are much less stable then the underlying duplex. Thirdly, parallel C⁺.GC and T.AT triplets and antiparallel G.GC, A.AT and T.AT triplets all involve third strand recognition of only the prime base of the duplex base pair. Moreover, there are no known base analogues that bind tightly to CG and TA inversions and display selectivity for these base pairs.

In this thesis some of the above limitations have been addressed. Cytosine analogues to overcome the pH dependency of the C⁺.GC interaction have been synthesised and evaluated. Studies of the bis-amino modified thymidine analogue (Bis-amino U) have demonstrated the importance of this analogue in improving the overall stability of the triplex, and pyrrolo-pyrimidinone analogues designed to recognise CG interruptions have been synthesised and studied.

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