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

By D.T. Hickman, T.H.S. Tan, J. Morral, Paul M. King, M.A. Cooper and J. Micklefield

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

Topics: bcs
Publisher: Royal Society of Chemistry
Year: 2003
OAI identifier: oai:eprints.bbk.ac.uk.oai2:83
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