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Chembiochem. 2017 Nov 2;18(21):2165-2170. doi: 10.1002/cbic.201700400. Epub 2017 Sep 26.

2-Methoxypyridine as a Thymidine Mimic in Watson-Crick Base Pairs of DNA and PNA: Synthesis, Thermal Stability, and NMR Structural Studies.

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Department of Chemistry, Binghamton University, The State University of New York, Binghamton, NY, 13902, USA.
Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, NY, 14642, USA.


The development of nucleic acid base-pair analogues that use new modes of molecular recognition is important both for fundamental research and practical applications. The goal of this study was to evaluate 2-methoxypyridine as a cationic thymidine mimic in the A-T base pair. The hypothesis was that including protonation in the Watson-Crick base pairing scheme would enhance the thermal stability of the DNA double helix without compromising the sequence selectivity. DNA and peptide nucleic acid (PNA) sequences containing the new 2-methoxypyridine nucleobase (P) were synthesized and studied by using UV thermal melting and NMR spectroscopy. Introduction of P nucleobase caused a loss of thermal stability of ≈10 °C in DNA-DNA duplexes and ≈20 °C in PNA-DNA duplexes over a range of mildly acidic to neutral pH. Despite the decrease in thermal stability, the NMR structural studies showed that P-A formed the expected protonated base pair at pH 4.3. Our study demonstrates the feasibility of cationic unnatural base pairs; however, future optimization of such analogues will be required.


DNA duplexes; cationic base pairs; modified nucleobases; peptide nucleic acids; unnatural base pairs

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