Development of topoisomerase I inhibitors on the basis of structural variation of oligonucleotides.

Human topoisomerase I is essential for virtually every cellular DNA growth processes and has been regarded as a prime target for anticancer drugs due to its critical role in releasing the topological stress of DNA for replication and transcription. It was discovered in the past years that besides su...

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Bibliographic Details
Main Author: Quek, Ngee Mien.
Other Authors: School of Physical and Mathematical Sciences
Format: Theses and Dissertations
Language:English
Published: 2011
Subjects:
Online Access:http://hdl.handle.net/10356/42860
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Institution: Nanyang Technological University
Language: English
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Summary:Human topoisomerase I is essential for virtually every cellular DNA growth processes and has been regarded as a prime target for anticancer drugs due to its critical role in releasing the topological stress of DNA for replication and transcription. It was discovered in the past years that besides supercoiled DNA, some linear duplex oligonucleotides are able to act as substrates of eukaryotic topoisomerase I in vitro as well. Inspired by the earlier breakthrough, the exploration and development of human topoisomerase I inhibitors on the basis of structural variation of oligonucleotides are described. Some modified oligonucleotides, LNA-containing oligonucleotide and intrinsically curved oligonucleotides with mismatched base pairs, were investigated and demonstrated as efficient human topoisomerase I inhibitors. With introduction of DNA modification and imperfections close to the topoisomerase I cleavage site, the enzyme can form covalent bond linkage with the oligonucleotides and result in its inhibitory effect on topoisomerase I in the relaxation reaction on supercoiled DNA. Going by the success of exploring the intrinsically curved DNA oligonucleotides as competitive inhibitors of topoisomerase I, the development and synthesis of different sizes of mini closed circular double stranded DNA were examined in order to explore the possibility of the mini-circle DNA as human topoisomerase I inhibitors. Small circular double stranded DNA of 54 base pairs was synthesized. Further optimization has to be done to form various sizes of mini-circle for the investigation of the inhibitory effect of these DNA oligonucleotides on human topoisomerase I.