Olefinic peptide nucleic acid (OPA)

Article abstract of DOI:10.1081/NCN-120022838

The olefinic peptide nucleic acid analogues (OPA) monomers containing the bases thymine and adenine were synthesised in 11 steps. Fully modified oligomers containing these units were prepared and their pairing properties assessed by means of UV-melting ex

Full text of DOI:10.1081/NCN-120022838

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Olefinic Peptide Nucleic Acid (OPA)
Daniel Gautschi a & Christian J. Leumann a b
a Department of Chemistry and Biochemistry , University of Bern , Bern, Switzerland
b Department of Chemistry and Biochemistry , University of Bern , Frelestrasse 3, CH-3012,
Bern, Switzerland
Published online: 31 Aug 2006.
To cite this article: Daniel Gautschi & Christian J. Leumann (2003) Olefinic Peptide Nucleic Acid (OPA), Nucleosides,
Nucleotides and Nucleic Acids, 22:5-8, 1211-1213, DOI: 10.1081/NCN-120022838
To link to this article: http://dx.doi.org/10.1081/NCN-120022838
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, Nos. 5–8, pp. 1211–1213, 2003
Olefinic Peptide Nucleic Acid (OPA)
*
Daniel Gautschi and Christian J. Leumann
Department of Chemistry and Biochemistry, University of Bern,
Bern, Switzerland
ABSTRACT
The olefinic peptide nucleic acid analogues (OPA) monomers containing the
bases thymine and adenine were synthesised in 11 steps. Fully modified oligomers
containing these units were prepared and their pairing properties assessed by
means of UV-melting experiments.
Polyamide or peptide nucleic acids (PNAs), first described in 1991,[1] are DNA
analogues based entirely on an achiral polyamide backbone. A key structural feature
of PNA monomers 1 is the central amide linker between the base and the backbone.
This tertiary amide functionality is conformationally labile and occurs in both the E-
and Z-rotameric forms in uncomplexed PNA. In PNA=PNA, PNA=DNA and
PNA=RNA duplexes, the carbonyl oxygen of the amide linker unit points uniformly
to the carboxy terminus of the strand. OPA[2] was designed to remove this ambigu-
ity. The central amide functionality is replaced by an isostructural, configurationally
stable C ¼ C double bond in either the E (2) or the Z (3) configuration.
*Correspondence: Christian J. Leumann, Department of Chemistry and Biochemistry,
University of Bern, Frelestrasse 3, CH-3012 Bern, Switzerland; E-mail: leumann@ioc.
unibe.ch.
1211
DOI: 10.1081/NCN-120022838
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

1212
Gautschi and Leumann
Figure 1. Chemical structure of the monomeric units of the different peptide nucleic acid
analogues.
Scheme 1. a) n-BuLi, THF, ꢀ78ꢁC, 10 min, then (CHO)n, r.t., 1.5 h (83%); b) Red-Al, THF,
addition 0ꢁC-r.t., then NIS, ꢀ78ꢁC, 10 min (90%); c) tBuPh2SiCl, imidazole, THF, r.t., 16 h
(97%); d) Reformatsky reagent: BrCH2 CO2Et, Zn, CH2(OCH3)2, reflux, 30 min; coupling:
Pd(PPh3)4, DMPU, 65ꢁC, 2 h (88%); e) PPTSA, EtOH, 45ꢁC, 2.5 h (80%); f) PPh3, LiN3,
CBr4, DMF, 0ꢁC, 16 h (68%); g) HFꢂPy=Py 1:9, CH3CN, r.t., 2.5 h; h) DIAD, PPh3, N3-ben-
zoylthymine, THF, r.t., 2 h, (74% over two steps); i) DIAD, PPh3, N6-benzoyladenine, DMF,
0ꢁC, 16 h, (50% over two steps); j) LiOH(aq) 1 M, Dioxane, 0ꢁC, 16 h, (74%); k) Lindlar-cata-
lyst, H2, MeOH, r.t., 16 h; l) MMt-Cl, Et3N, DMSO, 16 h, (65%).

Olefinic Peptide Nucleic Acid
1213
Table 1. Mass spectrometry data and Tm values [ꢁC] (UV-melting-curves, 260 nm) of PNA,
All-E-OPA and All-Z-OPA with parallel and antiparallel DNA (c ¼ 4 mM in 100 mM NaCl,
10 mM, Na2HPO4, pH 7.0).
Tm Tm
m=z found (antiparallel (parallel
m=z
calcd
Sequence
(ESIþTOF)
DNA)a
DNA)b
c
20 dC(ttttaatata)-Gly-NH2
3060.9
2891.0
3060.9
2891.3
2730.75
29.4
< 0
not detected
13.1
16.0
21.5
21 dC(tEtEtEtEaEaEtEaEtEaE)-Gly-NH2
22 Lys-tZtZtZtZaZaZtZaZtZaZ-Gly-NH2 2731.03
c
ad(TATATTAAAA).
bd(AAAATTATAT).
cData from 2.
The MMT-Z- OPA monomer 15 and 19, containing the bases thymine and ade-
nine, were now synthesised in 11 steps, starting from THP-protected-3-Butyn-1-ol.
The synthesis is outlined in Sch. 1.
In order to study the pairing properties, oligomers 20–22 were prepared using
the MMT-=Acyl-strategy,[3] and the stability of the duplexes formed with anti-par-
allel and parallel DNA was assessed by means of UV-melting curves (Table 1). All-
Z-OPA binds preferentially to parallel DNA (Tm ¼ 21ꢁC) rather than antiparallel
(no pairing detected). Thus it shows opposite strand alignment behavior compared
to PNA. This might be a consequence of the structural preorganisation of the mono-
meric unit, which mimics the rotameric form of PNA that is not observed in
complexes. The overall lower affinity to DNA compared to PNA seems to be a con-
sequence of differential solvation or dipole moment, rather than being of conforma-
tional origin.
REFERENCES
1. Nielsen, P.E.; Egholm, M.; Berg, R.H.; Burchardt, O. Science 1991, 254, 1497–
1500.
2. Schutz, R.; Cantin, M.; Roberts, C.; Greiner, B.; Uhlmann, E.; Leumann, C.
¨
Angew. Chem. Int. Ed. 2000, 39, 1250–1253.
3. Will, D.W.; Breipohl, G.; Langner, D.; Knolle, J.; Uhlmann, E. Tetrahedron
1995, 51, 12,069–12,082.