Foldamers derived from nucleoside β-amino acids: PNA or DNA? Can we have both in one place?

Article abstract of DOI:10.1080/15257770701490399

The synthesis of a modified thymidine (nucleoside β-amino acid) monomer and preliminary investigations into the solid phase peptide synthesis of PNA/DNA chimeras containing a neutral, internucleoside amide linkage are described. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/15257770701490399

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Nucleosides, Nucleotides and Nucleic
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Foldamers Derived From Nucleoside β-
Amino Acids: Pna Or Dna? Can We Have
Both In One Place?
Richard Threlfall a , Andrew Davies a , Nicola Howarth b & Richard
Cosstick a
a Department of Chemistry , University of Liverpool , Liverpool,
United Kingdom
b School of Engineering and Physical Sciences , Heriot-Watt
University , Riccarton, Edinburgh, United Kingdom
Published online: 10 Dec 2007.
To cite this article: Richard Threlfall , Andrew Davies , Nicola Howarth & Richard Cosstick (2007)
Foldamers Derived From Nucleoside β-Amino Acids: Pna Or Dna? Can We Have Both In One Place?,
Nucleosides, Nucleotides and Nucleic Acids, 26:6-7, 611-614, DOI: 10.1080/15257770701490399
To link to this article: http://dx.doi.org/10.1080/15257770701490399
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Nucleosides, Nucleotides, and Nucleic Acids, 26:611–614, 2006
Copyright ꢀ Taylor & Francis Group, LLC
C
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701490399
FOLDAMERS DERIVED FROM NUCLEOSIDE β-AMINO ACIDS:
PNA OR DNA? CAN WE HAVE BOTH IN ONE PLACE?
Richard Threlfall and Andrew Davies
Department of Chemistry, University
2
of Liverpool, Liverpool, United Kingdom
Nicola Howarth
School of Engineering and Physical Sciences, Heriot-Watt
2
University, Riccarton, Edinburgh, United Kingdom
Richard Cosstick
Department of Chemistry, University of Liverpool, Liverpool,
2
United Kingdom
The synthesis of a modified thymidine (nucleoside β-amino acid) monomer and preliminary
2
investigations into the solid phase peptide synthesis of PNA/DNA chimeras containing a neutral,
internucleoside amide linkage are described.
Keywords Peptide nucleic acid; chimera; foldamers; nucleoside beta-amino acid
INTRODUCTION
The majority of natural biological processes rely on macromolecules
with defined tertiary structures, the most obvious examples being RNA and
protein catalysis. The specificity of these macromolecules is derived from
their ability to adopt compact folded architectures, which, in turn, are as-
semblies of secondary structure motifs, such as helices and sheets. Unnatu-
ral oligomers that display similar propensity to adopt conformers are termed
“foldamers”.[1] Even with the emergence of peptide nucleic acid (PNA),[2]
there has only been limited exploration into combining the structural po-
tential of nucleosides (predictable nucleobase association) and the peptide
bond. The synthesis of a novel nucleoside β-amino acid has been completed.
Derived from thymidine, the compound contains a 5ꢁ-carboxylic acid moi-
ety and a 3ꢁ-amino function to enable the construction of peptide bonds
by standard solid-phase peptide synthesis procedures. Investigation into the
synthesis of an amide-backboned oligonucleotide/polypeptide hybrid is cur-
rently underway.
Address correspondence to Richard Threlfall, Department of Chemistry, University of Liverpool,
Crown Street, Liverpool L69 72D, UK. E-mail: r.threlfall@liv.ac.uk
611

612
R. Threlfall et al.
SCHEME 1
RESULTS AND DISCUSSION
The synthesis of the target Fmoc-protected nucleoside β-amino
acid (mT, see Scheme 1) was achieved beginning with the 3ꢁ-azido-3ꢁ-
deoxythymidine (AZT) synthesis of Czernecki et al.[3]. Starting from thymi-
dine, two Mitsunobu style reactions performed in tandem allowed sequen-
tial, one-pot protection of 5ꢁ-OH with a PMB group whilst stereoselectively
displacing 3ꢁ-OH by forming the anhydro compound (1) using neighboring
group participation from the heterocyclic base. Yields of the anhydro species
were improved by more than 10% over that obtained at room temperature
by cooling the reaction mixture to a constant 15◦C in a water bath during
exothermic DIAD additions. The anhydro species was then opened from
the α-face by N−3 in DMF at 125◦C. Little difference in yield was observed
using either NaN3 or LiN3, both giving around 50% yield after purification.
Attempts to improve the yield by the addition of a proton source (benzoic
acid) to assist in the reprotonation of thymine N3 also made very little dif-
ference to the overall yield.
By far the simplest method for reduction of the 3ꢁ-azide was catalytic hy-
drogenation over Pd/C giving the 3ꢁ-amino compound a 97% yield. Fmoc
protection of the 3ꢁ-amine was afforded by treatment of (2) with FmocCl
and K2CO3 in aqueous 1,4-dioxane. From many available, the method cho-
sen for oxidation of the 5ꢁ-OH was using free radical TEMPO and hyperva-
lent iodine complex (bis-acetoxy)-iodobenzene (BAIB).[4] In the standard

Foldamers from Nucleoside β-Amino Acids
613
SCHEME 2
solvent for this reaction (aqueous acetonitrile) the Fmoc-protected nucleo-
side is only sparingly soluble, leading to reaction times of greater than 24
hours and low yields of around 45%.
It was believed that these neutral-backboned oligomers would not be
readily soluble in aqueous media and that natural α-amino acids should be
included in an attempt to improve aqueous solubility. Therefore, it was de-
cided that lysine residues should be included at both C- and N -terminals
(see Scheme 2). Initial studies on oligomerisation of the Fmoc-protected nu-
cleoside β-amino acid were based on the method of Gude et al.[5] Loading
of Fmoc-Lys-(monomethyltrityl)-OH onto the solid support (Sieber amide
resin) was determined by UV assay of dibenzofulvene at λ = 294 and 304
nm liberated during the deblocking step.
The technique was also extended to the first two couplings of mT to
inspect the coupling efficiencies with the natural amino acid and with
itself. This qualitative method was sufficient to show that little differ-
ence was observed for the coupling of lysine to mT when using either
Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate
(PyBOP) or 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium hexaflu-
orophosphate (HBTU) as the coupling reagent. However, NMP and DMF
were particulary poor solvents. The mT to mT couplings were also solvent
dependent. In this case, coupling yields were significantly reduced using the

614
R. Threlfall et al.
combination of HBTU with DMF but increased greatly with the addition of
20% DMSO. The superior solvent/coupling reagent combination was found
to be N ,N ,-dimethylacetamide with HBTU.
CONCLUSIONS
The modified thymidine monomer, mT, has been synthesized success-
fully in reasonable yield from thymidine and the production of oligomers
via solid-phase peptide synthesis protocols is currently under investigation.
REFERENCES
1. Gellman, S.H. Foldamers: A manifesto. Accounts Chem. Res. 1998, 31, 173–180.
2. Nielsen, P.E.; Egholm, M.; Berg, R.H.; Buchardt, O. Sequence-selective recognition of DNA by strand
displacement with a thymine-substituted polyamide. Science 1991, 254, 1497–1500.
3. Czernecki, S.; Valery, J.M. An efficient synthesis of 3ꢁ-Azido-3ꢁ-deoxythymidine (AZT). Synthesis 1991,
239–240.
4. Epp, J.B.; Widlanski, T.S. Facile preparation of nucleoside-5ꢁ-carboxylic acids. J. Org. Chem. 1999, 64,
293–295.
5. Gude, M.; Ryf, J.; White, P.D. An accurate method for the quantitation of Fmoc-derivatized solid
phase supports. Lett. Pept. Sci. 2002, 9, 203–206.