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Design, synthesis, conformational analysis and nucleic acid hybridisation properties of thymidyl pyrrolidine-amide oligonucleotide mimics (POM)

Hickman, D.T. and Tan, T.H.S. and Morral, J. and King, Paul M. and Cooper, M.A. and Micklefield, J. (2003) Design, synthesis, conformational analysis and nucleic acid hybridisation properties of thymidyl pyrrolidine-amide oligonucleotide mimics (POM). Organic & Biomolecular Chemistry 1 (19), pp. 3277-3292. ISSN 1477-0520.

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Abstract

Pyrrolidine-amide oligonucleotide mimics (POM) 1 were designed to be stereochemically and conformationally similar to natural nucleic acids, but with an oppositely charged, cationic backbone. Molecular modelling reveals that the lowest energy conformation of a thymidyl-POM monomer is similar to the conformation adopted by ribonucleosides. An e cient solution phase synthesis of the thymidyl POM oligomers has been developed, using both N-alkylation and acylation coupling strategies. 1H NMR spectroscopy con rmed that the highly water soluble thymidyl-dimer, T2-POM, preferentially adopts both a con guration about the pyrrolidine N-atom and an overall conformation in D2O that are very similar to a typical C3 -endo nucleotide in RNA. In addition the nucleic acid hybridisation properties of a thymidyl-pentamer, T5-POM, with an N-terminal phthalimide group were evaluated using both UV spectroscopy and surface plasmon resonance (SPR). It was found that T5-POM exhibits very high a nity for complementary ssDNA and RNA, similar to that of a T5-PNA oligomer. SPR experiments also showed that T5-POM binds with high sequence delity to ssDNA under near physiological conditions. In addition, it was found possible to attenuate the binding a nity of T5-POM to ssDNA and RNA by varying both the ionic strength and pH. However, the most striking feature exhibited by T5-POM is an unprecedented kinetic binding selectivity for ssRNA over DNA.

Item Type: Article
School or Research Centre: Birkbeck Schools and Research Centres > School of Science > Biological Sciences
Depositing User: King P M
Date Deposited: 28 Feb 2005
Last Modified: 17 Apr 2013 12:32
URI: http://eprints.bbk.ac.uk/id/eprint/83

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