Tetrahedron Letters
Synthesis of
a-PNA containing a functionalized triazine
as nucleobase analogue
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Eline Bartolami , Arnaud Gilles , Pascal Dumy, Sébastien Ulrich
Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-Université Montpellier-ENSCM, Ecole Nationale Supérieure de Chimie de Montpellier,
8 Rue de l’Ecole Normale, 34296 Montpellier cedex 5, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The design of artificial structures such as Peptide Nucleic Acids (PNAs) capable of recognizing nucleic
Received 3 February 2015
Revised 13 March 2015
Accepted 17 March 2015
Available online 22 March 2015
acids has attracted much attention. We report herein the design of L-homoserine derivatives bearing
diaminotriazine groups as artificial nucleobase capable of pairing to thymine. We set up an original
six-step synthetic route (45% overall yield) that enables the functionalization of the nucleobase analogue.
Furthermore, we show that these modified amino acids can be incorporated, by solid-phase peptide syn-
thesis, into alternate and homopolymer a-PNAs, thereby giving access to a-PNAs in which the nucleobase
analogue bears functional groups that may prove useful for the multi-point recognition of nucleic acids.
Keywords:
Peptide nucleic acid
Triazine
Ó 2015 Elsevier Ltd. All rights reserved.
Artificial nucleobase
Multi-point recognition
Introduction
to confer enhanced potency to antisense phosphorothioate
oligodeoxynucleotide.10 More recently, it has been shown that
The design of functionalized ligands of biomolecules is of great
interest for applications in health sciences.1 On the one hand, the
ability to tether molecular reporters without affecting the binding
affinity of the ligand for its target may serve for sensing and imag-
ing applications. On the other hand, the presence of side-groups
that directly interact with the target through additional non-cova-
lent interactions may be useful for enhancing the binding affinity
and selectivity through multi-point recognition.2 For instance, it
has recently been shown that side groups present on glycopoly-
mers have an effect on the recognition of lectins.3
In the field of oligonucleotide recognition, various chemical
functionalizations,4 or chemical modifications of the inter-nucleo-
tidic linkage,5 sugar moiety,6 and nucleobase5b,7 have been
introduced into oligonucleotides to tune their stability and
recognition properties for a specific application such as antisense
technology.1,8 In particular, functionalization of the nucleobase
has been exploited for multi-point binding. For instance, func-
tionalized cytosine analogues capable of ‘clamp-like’ binding
through a combination of Watson–Crick pairing and hydrogen
bonding on the Hoogsteen edge of the base pair9 have been shown
the presence of additional side-groups that enhance p-stacking
interactions greatly improves the selectivity of a novel nucleobase
analogue for its complementary DNA partner.11 It is therefore
important, for promoting hybridization with nucleic acids, to
develop synthetic methodologies that enable the construction of
biomolecular conjugates featuring functionalized nucleobases
tethered to an organic scaffold.
The instability in biological media and the poor cellular pene-
tration properties of natural oligonucleotides have spurred interest
in alternative artificial scaffolds that are capable of hybridizing
with nucleic acids. Peptide-based scaffolds that interact with
nucleic acids have attracted considerable interest, both for the
study of prebiotic informational systems,12 and for applications
in biotechnology. Indeed, peptide-based scaffolds can be readily
synthesized and further functionalized in a modular fashion.
Peptide Nucleic Acids (PNAs) have been identified as an artificial
class of peptide-based compounds that hybridize effectively with
nucleic acids.13 PNA feature a scaffold made of a repetition of N-
(2-aminoethyl)-glycine moiety appended with nucleobases as
side-chains. Functionalization of the scaffold has been shown to
affect the stability of PNA–DNA and PNA–RNA duplexes.14
Artificial nucleobases have also been placed onto PNA scaffolds.
Cyanuryl groups have thus been proposed as thymine mimic,15
while the insertion of 2-aminopyridine has been reported to lead
to triplex formation with double-stranded RNA under physiologi-
cal conditions.16
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Corresponding author. Tel.: +33 467144346; fax: +33 467144353.
These authors contributed equally to this work.
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.