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

Hickman, D. T., Tan, T.H.S., Morral, J., King, P.M., Cooper, Matthew 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: 3277-3292. doi:10.1039/b306156f


Author Hickman, D. T.
Tan, T.H.S.
Morral, J.
King, P.M.
Cooper, Matthew A.
Micklefield, J.
Title Design, synthesis, conformational analysis and nucleic acid hybridisation properties of thymidyl pyrrolidine-amide oligonucleotide mimics (POM)
Journal name Organic & Biomolecular Chemistry   Check publisher's open access policy
ISSN 1477-0520
Publication date 2003-01-01
Year available 2003
Sub-type Article (original research)
DOI 10.1039/b306156f
Open Access Status Not Open Access
Volume 1
Issue 19
Start page 3277
End page 3292
Total pages 16
Place of publication Cambridge, United Kingdom
Publisher Royal Society of Chemistry
Language eng
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 efficient solution phase synthesis of the thymidyl POM oligomers has been developed, using both N-alkylation and acylation coupling strategies. 1H NMR spectroscopy confirmed that the highly water soluble thymidyl-dimer, T2-POM, preferentially adopts both a configuration 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 affinity for complementary ssDNA and RNA, similar to that of a T5-PNA oligomer. SPR experiments also showed that T5-POM binds with high sequence fidelity to ssDNA under near physiological conditions. In addition, it was found possible to attenuate the binding affinity 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.
Keyword Deoxyribonucleic Guanidine
Backbone modification
Reversed nucleosides
Versatile tool
Amino-acids
DNA
Peptide
RNA
Binding
PNA
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
Institute for Molecular Bioscience - Publications
 
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Created: Tue, 17 Nov 2009, 22:17:12 EST