NOVEL PEPTIDE NUCLEIC ACID MONOMERS FROM TRIPLEX-FORMING BASES

1
NOVEL PEPTIDE NUCLEIC ACID MONOMERSFROM
TRIPLEX-FORMING BASES
Zoltán Timára, Péter Forgób, Zoltán Kelea, Lajos
Kovácsa, University of Szeged, aDepartment of
Medicinal Chemistry and bDepartment of Organic
Chemistry, 6720 Szeged, Dóm tér 8, Hungary.
E-mail kovacs_at_ovrisc.mdche.u-szeged.hu
Introduction
Oligonucleotide-directed triple-helix formation
is one of the most powerful methods for the
sequence-specific recognition of double-helical
DNA. According to our previous theoretical
calculations,1 the artificial nucleobases
containing 2-aminopyridine (N) and
2-aminoquinoline (Q) moieties, respectively, deem
to be good candidates as universal triple
helix-forming agents both for the AT and TA
base pairs by Hoogsteen-type H-bonding. So far
compounds capable to selectively bind to both
strands of DNA have not been prepared. On the
other hand, peptide nucleic acids (PNA) are very
promising nucleic acid mimics.2 We wish to report
herein our efforts directed toward the chemical
synthesis of PNA monomers containing the above
triplex-forming heterocycles.
Geometry of the natural triplex-forming
nucleobases (CGC, CGG, TAT and TAA.
Colon Watson-Crick, vertical bar Hoogsteen-type
binding)
Geometry of the designed triplex-forming
nucleobases (TAN and QAT)
Isomorphism of the natural and designed triplex-fo
rming nucleobases
Results
The 2-aminopyridine (N) unit was prepared
starting from ethyl 3-pyridylacetate using the
procedure by Wachi et al.3 but the yields were
rather low therefore an alternative approach was
sought. Thus, the same starting material was
subjected to Minisci reaction with formamide4 and
subsequent Hofmann degradation is in progress.
N
The 2-aminoquinoline (Q) unit was prepared from
3-methyl-4-nitrobenzoic acid through the
3-carbaldehyde followed by a Horner-Wadsworth-Emmo
ns chain elongation. The reduction and
cyclisation of the 3-(2-cyanovinyl) derivative to
the desired quinoline was accomplished using
tin(II) salts or, preferably, sodium dithionite.
The latter method made the purification of the
product more convenient. The acids protected with
anisoyl and 4-tert-butylbenzoyl groups will be
coupled to Fmoc-protected tert-butyl
N-(2-aminoethyl)glicinate and their use in the
synthesis of the corresponding PNA oligomers is
in progress.
Q
References
1. R. Fenyõ, Z. Timár, I. Pálinkó and B. Penke
(2000) J. Mol. Struct. (Theochem), 496,
101-105. 2. P. E. Nielsen (1999) Peptide nucleic
acid. A molecule with two identities. Acc. Chem.
Res. 32, 624-630. 3. K. Wachi and A. Terada
(1980) Chem. Pharm. Bull., 28, 465-472. 4. J. A.
Joule, K. Mills and G. F. Smith (1995)
Heterocyclic chemistry. 3rd ed. Chapman and Hall,
London. p. 26.