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

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Abstract

Pyrrolidine-amide oligonucleotide mimics (POM) I [B = adenine (A), thymine (T), cytosine (C), guanine (G)] were designed to be stereochem. and conformationally similar to natural nucleic acids, but with an oppositely charged, cationic backbone. Mol. modeling reveals that the lowest energy conformation of a thymidyl-POM monomer is similar to the conformation adopted by ribonucleosides. An efficient soln. 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 sol. 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 addn. the nucleic acid hybridization 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 expts. also showed that T5-POM binds with high sequence fidelity to ssDNA under near physiol. conditions. In addn., 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. [on SciFinder (R)]

Keyword(s)

Alkylation Amidation (coupling strategy for soln. phase synthesis of the thymidyl POM oligomers prepn., conformational anal. and nucleic acid hybridization properties of thymidyl pyrrolidine-amide oligonucleotide mimics) Molecular modeling (lowest energy conformation prepn., conformational anal. and nucleic acid hybridization properties of thymidyl pyrrolidine-amide oligonucleotide mimics) Reaction kinetics (of hybridization prepn., conformational anal. and nucleic acid hybridization properties of thymidyl pyrrolidine-amide oligonucleotide mimics) Configuration Conformation Nucleic acid hybridization Surface plasmon resonance (prepn., conformational anal. and nucleic acid hybridization properties of thymidyl pyrrolidine-amide oligonucleotide mimics) Oligonucleotides Role: PRP (Properties), SPN (Synthetic preparation), PREP (Preparation) (thymidyl pyrrolidine-amide mimics prepn., conformational anal. and nucleic acid hybridization properties of thymidyl pyrrolidine-amide oligonucleotide mimics)

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