Fluorinated olefinic peptide nucleic acid: synthesis and pairing properties with complementary DNA

Hollenstein, Marcel; Leumann, Christian J. (2005). Fluorinated olefinic peptide nucleic acid: synthesis and pairing properties with complementary DNA. Journal of organic chemistry, 70(8), pp. 3205-3217. American Chemical Society 10.1021/jo047753e

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The fluorinated olefinic peptide nucleic acid (F-OPA) system was designed as a peptide nucleic acid (PNA) analogue in which the base carrying amide moiety was replaced by an isostructural and isoelectrostatic fluorinated C-C double bond, locking the nucleobases in one of the two possible rotameric forms. By comparison of the base-pairing properties of this analogue with its nonfluorinated analogue OPA and PNA, we aimed at a closer understanding of the role of this amide function in complementary DNA recognition. Here we present the synthesis of the F-OPA monomer building blocks containing the nucleobases A, T, and G according to the MMTr/Acyl protecting group scheme. Key steps are a selective desymmetrization of the double bond in the monomer precursor via lactonization as well as a highly regioselective Mitsunobu reaction for the introduction of the bases. PNA decamers containing single F-OPA mutations and fully modified F-OPA decamers and pentadecamers containing the bases A and T were synthesized by solid-phase peptide chemistry, and their hybridization properties with complementary parallel and antiparallel DNA were assessed by UV melting curves and CD spectroscopic methods. The stability of the duplexes formed by the decamers containing single (Z)-F-OPA modifications with parallel and antiparallel DNA was found to be strongly dependent on their position in the sequence with T(m) values ranging from +2.4 to -8.1 degrees C/modification as compared to PNA. Fully modified F-OPA decamers and pentadecamers were found to form parallel duplexes with complementary DNA with reduced stability compared to PNA or OPA. An asymmetric F-OPA pentadecamer was found to form a stable self-complex (T(m) approximately 65 degrees C) of unknown structure. The generally reduced affinity to DNA may therefore be due to an increased propensity for self-aggregation

Item Type:

Journal Article (Original Article)


08 Faculty of Science > Department of Chemistry, Biochemistry and Pharmaceutical Sciences (DCBP)

UniBE Contributor:

Hollenstein, Marcel, Leumann, Christian


500 Science > 570 Life sciences; biology
500 Science > 540 Chemistry




American Chemical Society




Christian Leumann

Date Deposited:

26 May 2014 15:57

Last Modified:

05 Dec 2022 14:34

Publisher DOI:


PubMed ID:


Uncontrolled Keywords:

ACID, Alkenes, amide, analogue, antiparallel, base, Base Pairing, BASE-PAIRING PROPERTIES, bases, BUILDING-BLOCKS, CD, chemical synthesis, chemistry, Chemistry, Physical, Circular Dichroism, DNA, DNA recognition, DNA Complementary, double, duplex, DUPLEXES, Fluorine, Guanine, hybridization, HYBRIDIZATION PROPERTIES, Indicators and Reagents, methods, modified, Molecular Structure, Mutation, nucleobases, OPA, PAIRING PROPERTIES, parallel, peptide, Peptide Nucleic Acids PNA, properties, recognition, Research Support,Non-U.S.Gov't, solid phase, Spectrum Analysis, Mass, stability, Stereoisomerism, Structure, synthesis, THYMINE





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